{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:15:56Z","timestamp":1777479356956,"version":"3.51.4"},"reference-count":200,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T00:00:00Z","timestamp":1557187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation. Interestingly, a number of approved therapeutic agents, such as cyclosporine, steroid hormones, and thiazolidinediones, actually function by affecting enhancer landscapes by directly targeting very specific transcription factor programs. More recently, a broader approach to targeting deregulated enhancer programs has been achieved via Bromodomain and Extraterminal (BET) inhibition or perturbation of transcription-related cyclin-dependent kinases (CDK). One challenge to enhancer-targeted therapy is proper patient stratification. We suggest that monitoring of enhancer RNA (eRNA) expression may serve as a unique biomarker of enhancer activity that can help to predict and monitor responsiveness to enhancer-targeted therapies. A more thorough investigation of cancer-specific enhancers and the underlying mechanisms of deregulation will pave the road for an effective utilization of enhancer modulators in a precision oncology approach to cancer treatment.<\/jats:p>","DOI":"10.3390\/cancers11050634","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T03:57:07Z","timestamp":1557719827000},"page":"634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Perturbing Enhancer Activity in Cancer Therapy"],"prefix":"10.3390","volume":"11","author":[{"given":"Feda H.","family":"Hamdan","sequence":"first","affiliation":[{"name":"Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-5805","authenticated-orcid":false,"given":"Steven A.","family":"Johnsen","sequence":"additional","affiliation":[{"name":"Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13557","DOI":"10.1093\/nar\/gku885","article-title":"Aberrant transcriptional regulations in cancers: Genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines","volume":"42","author":"Suzuki","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.ccell.2018.10.015","article-title":"A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence","volume":"34","author":"Lu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2016.12.013","article-title":"Transcriptional Addiction in Cancer","volume":"168","author":"Bradner","year":"2017","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrg3207","article-title":"Transcription factors: From enhancer binding to developmental control","volume":"13","author":"Spitz","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","first-page":"4526","article-title":"Multiple hormone-inducible enhancers as mediators of differential transcription","volume":"6","author":"Toohey","year":"1986","journal-title":"Mol. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.cell.2013.09.053","article-title":"Super-enhancers in the control of cell identity and disease","volume":"155","author":"Hnisz","year":"2013","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nature14154","article-title":"Super-enhancers delineate disease-associated regulatory nodes in T cells","volume":"520","author":"Vahedi","year":"2015","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, W., Yao, S., Tang, J., Liu, S., Chen, J., Deng, D., and Zeng, C. (2018). Integrative analysis of super enhancer SNPs for type 2 diabetes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192105"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cell.2014.02.019","article-title":"A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia","volume":"157","author":"Groschel","year":"2014","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.cell.2018.05.037","article-title":"A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer","volume":"174","author":"Takeda","year":"2018","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41588-018-0044-9","article-title":"Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma","volume":"50","author":"Zeid","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature13379","article-title":"Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma","volume":"511","author":"Northcott","year":"2014","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.cell.2017.07.007","article-title":"Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis","volume":"170","author":"Roe","year":"2017","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/j.celrep.2018.10.051","article-title":"TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma","volume":"25","author":"Somerville","year":"2018","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E12343","DOI":"10.1073\/pnas.1812915116","article-title":"DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network","volume":"115","author":"Hamdan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/ng.2913","article-title":"An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia","volume":"46","author":"Knoechel","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/nsmb.2784","article-title":"Enhancer biology and enhanceropathies","volume":"21","author":"Smith","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fgene.2012.00195","article-title":"Transcription factor binding at enhancers: Shaping a genomic regulatory landscape in flux","volume":"3","author":"Palstra","year":"2012","journal-title":"Front. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.cell.2018.01.029","article-title":"The Human Transcription Factors","volume":"172","author":"Lambert","year":"2018","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1101\/gad.176826.111","article-title":"Pioneer transcription factors: Establishing competence for gene expression","volume":"25","author":"Zaret","year":"2011","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/nar\/gkw826","article-title":"BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire","volume":"45","author":"Najafova","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7690","DOI":"10.1093\/nar\/gks501","article-title":"Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages","volume":"40","author":"Lan","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wu, Y., Zeng, J., Roscoe, B.P., Liu, P., Yao, Q., Lazzarotto, C.R., Clement, K., Cole, M.A., Luk, K., and Baricordi, C. (2019). Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nature Med.","DOI":"10.1038\/s41591-019-0401-y"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tsang, F.H., Law, C.T., Tang, T.C., Cheng, C.L., Chin, D.W., Tam, W.V., Wei, L., Wong, C.C., Ng, I.O., and Wong, C.M. (2019). Aberrant Super-Enhancer Landscape in Human Hepatocellular Carcinoma. Hepatology.","DOI":"10.1002\/hep.30544"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.cell.2013.06.044","article-title":"CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes","volume":"154","author":"Gilbert","year":"2013","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e45973","DOI":"10.7554\/eLife.45973","article-title":"Gene activation by a CRISPR-assisted trans enhancer","volume":"8","author":"Xu","year":"2019","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1801423","DOI":"10.1002\/advs.201801423","article-title":"Multistage Delivery Nanoparticle Facilitates Efficient CRISPR\/dCas9 Activation and Tumor Growth Suppression In Vivo","volume":"6","author":"Liu","year":"2018","journal-title":"Adv. Sci. (Weinh)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1136\/bmj.1.5844.13","article-title":"Anti-oestrogen therapy for breast cancer: A trial of tamoxifen at two dose levels","volume":"1","author":"Ward","year":"1973","journal-title":"Br. Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/1097-0142(197803)41:3<797::AID-CNCR2820410303>3.0.CO;2-7","article-title":"The use of antiestrogens tamoxifen and nafoxidine in the treatment of human breast cancer in correlation with estrogen receptor values. A phase II study","volume":"41","author":"Moseson","year":"1978","journal-title":"Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/1097-0142(197902)43:2<444::AID-CNCR2820430207>3.0.CO;2-C","article-title":"Antihormone treatment of stage IV breast cancer","volume":"43","author":"Manni","year":"1979","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1159\/000179775","article-title":"New hormonal therapy in prostate cancer: Combined use of a pure antiandrogen and an LHRH agonist","volume":"18","author":"Labrie","year":"1983","journal-title":"Horm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0022-4731(86)90043-9","article-title":"Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer","volume":"24","author":"Moguilewsky","year":"1986","journal-title":"J. Steroid Biochem."},{"key":"ref_33","first-page":"30","article-title":"Newer methods of hormonal therapy for prostate cancer","volume":"24","author":"Soloway","year":"1984","journal-title":"Urology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1073\/pnas.71.10.3901","article-title":"Receptors from glucocorticoid-sensitive lymphoma cells and two clases of insensitive clones: Physical and DNA-binding properties","volume":"71","author":"Yamamoto","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.1073\/pnas.69.11.3124","article-title":"Glucocorticoid action on hybrid clones derived from cultured myeloma and lymphoma cell lines","volume":"69","author":"Gehring","year":"1972","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"596","DOI":"10.2174\/092986713804999303","article-title":"Treatment of estrogen receptor-positive breast cancer","volume":"20","author":"Lumachi","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/rmb2.12006","article-title":"Molecular mechanism of estrogen-estrogen receptor signaling","volume":"16","author":"Yasar","year":"2017","journal-title":"Reprod. Med. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/ng1901","article-title":"Genome-wide analysis of estrogen receptor binding sites","volume":"38","author":"Carroll","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41594-019-0190-5","article-title":"Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly","volume":"26","author":"Nair","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cell.2017.02.007","article-title":"A Phase Separation Model for Transcriptional Control","volume":"169","author":"Hnisz","year":"2017","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1093\/nar\/gkp352","article-title":"Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers","volume":"37","author":"Makkonen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10006","article-title":"Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA","volume":"474","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_43","first-page":"312","article-title":"Tissue-specific pioneer factors associate with androgen receptor cistromes and transcription programs","volume":"33","author":"Pihlajamaa","year":"2014","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1101\/gr.233346.117","article-title":"Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding","volume":"28","author":"McDowell","year":"2018","journal-title":"Genome Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e1658","DOI":"10.1038\/cddis.2015.14","article-title":"The calcineurin\/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells","volume":"6","author":"Quang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_46","first-page":"465","article-title":"PPAR-gamma ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity","volume":"19","author":"Takashima","year":"2001","journal-title":"Int. J. Oncol."},{"key":"ref_47","first-page":"1409","article-title":"The ligands of peroxisome proliferator-activated receptor (PPAR) gamma inhibit growth of human esophageal carcinoma cells through induction of apoptosis and cell cycle arrest","volume":"24","author":"Fujii","year":"2004","journal-title":"Anticancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/ijc.11561","article-title":"Growth arrest by troglitazone is mediated by p27Kip1 accumulation, which results from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells","volume":"108","author":"Motomura","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1051\/bmdcn\/2019090104","article-title":"Association between colorectal cancer and thiazolidinediones administration in a case-control study","volume":"9","author":"Liao","year":"2019","journal-title":"BioMedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: Regulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1007\/s10620-012-2255-8","article-title":"Calcineurin\/NFATc1 pathway contributes to cell proliferation in hepatocellular carcinoma","volume":"57","author":"Wang","year":"2012","journal-title":"Dig. Dis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1038\/jid.2012.179","article-title":"NFATc2 is a potential therapeutic target in human melanoma","volume":"132","author":"Perotti","year":"2012","journal-title":"J. Invest. Dermatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1083\/jcb.200901104","article-title":"FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1","volume":"185","author":"Norrmen","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1158\/2159-8290.CD-13-0593","article-title":"Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D","volume":"4","author":"Baumgart","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1038\/sj.emboj.7601246","article-title":"Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+\/calcineurin signaling pathway","volume":"25","author":"Buchholz","year":"2006","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nature08996","article-title":"Opposing roles for calcineurin and ATF3 in squamous skin cancer","volume":"465","author":"Wu","year":"2010","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.2353\/ajpath.2010.090972","article-title":"HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers","volume":"176","author":"Baba","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.18632\/oncotarget.13605","article-title":"Down regulation of RNA binding motif, single-stranded interacting protein 3, along with up regulation of nuclear HIF1A correlates with poor prognosis in patients with gastric cancer","volume":"8","author":"Wu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_59","first-page":"1627","article-title":"Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells","volume":"37","author":"Ahn","year":"2010","journal-title":"Int. J. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1073\/pnas.94.9.4273","article-title":"A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development","volume":"94","author":"Ema","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bbagrm.2014.10.006","article-title":"Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10","volume":"1849","author":"Tausendschon","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1158\/0008-5472.CAN-03-3139","article-title":"Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications","volume":"64","author":"Rapisarda","year":"2004","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.cell.2008.01.018","article-title":"FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription","volume":"132","author":"Lupien","year":"2008","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.7150\/ijbs.26605","article-title":"Genome-wide Identification and Characterization of Enhancers Across 10 Human Tissues","volume":"14","author":"Xiong","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/ng.3950","article-title":"Reconstruction of enhancer-target networks in 935 samples of human primary cells, tissues and cell lines","volume":"49","author":"Cao","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E2191","DOI":"10.1073\/pnas.1320308111","article-title":"Global view of enhancer-promoter interactome in human cells","volume":"111","author":"He","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4349","DOI":"10.1158\/1078-0432.CCR-14-0494","article-title":"Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival","volume":"20","author":"Hu","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ccell.2018.02.003","article-title":"Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors","volume":"33","author":"Andricovich","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.ccr.2013.11.003","article-title":"Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma","volume":"24","author":"Chapuy","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6320","DOI":"10.1158\/0008-5472.CAN-16-0854","article-title":"BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer","volume":"76","author":"Yokoyama","year":"2016","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1158\/2159-8290.CD-16-0653","article-title":"Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex","volume":"7","author":"Zawistowski","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.celrep.2014.06.016","article-title":"Bromodomain protein BRD4 is required for estrogen receptor-dependent enhancer activation and gene transcription","volume":"8","author":"Nagarajan","year":"2014","journal-title":"Cell Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/nm.3952","article-title":"Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma","volume":"21","author":"Mazur","year":"2015","journal-title":"Nature Med."},{"key":"ref_74","first-page":"E4946","article-title":"Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia","volume":"111","author":"Wang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cell.2013.03.036","article-title":"Selective inhibition of tumor oncogenes by disruption of super-enhancers","volume":"153","author":"Loven","year":"2013","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nrg.2016.59","article-title":"The molecular hallmarks of epigenetic control","volume":"17","author":"Allis","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2010.08.011","article-title":"The language of histone crosstalk","volume":"142","author":"Lee","year":"2010","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1038\/nsmb.2436","article-title":"Perceiving the epigenetic landscape through histone readers","volume":"19","author":"Musselman","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/20974","article-title":"Structure and ligand of a histone acetyltransferase bromodomain","volume":"399","author":"Dhalluin","year":"1999","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nrd4286","article-title":"Targeting bromodomains: Epigenetic readers of lysine acetylation","volume":"13","author":"Filippakopoulos","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"19754","DOI":"10.1073\/pnas.1310658110","article-title":"RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain","volume":"110","author":"Picaud","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1016\/j.bmcl.2012.01.125","article-title":"From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151","volume":"22","author":"Mirguet","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.cell.2013.03.035","article-title":"Master transcription factors and mediator establish super-enhancers at key cell identity genes","volume":"153","author":"Whyte","year":"2013","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ng.3470","article-title":"Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers","volume":"48","author":"Zhang","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_85","first-page":"3693","article-title":"Inducible super-enhancers are organized based on canonical signal-specific transcription factor binding elements","volume":"45","author":"Bojcsuk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Gerard, D., Schmidt, F., Ginolhac, A., Schmitz, M., Halder, R., Ebert, P., Schulz, M.H., Sauter, T., and Sinkkonen, L. (2018). Temporal enhancer profiling of parallel lineages identifies AHR and GLIS1 as regulators of mesenchymal multipotency. Nucleic Acids Res.","DOI":"10.1101\/183988"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"14400","DOI":"10.1038\/ncomms14400","article-title":"Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome","volume":"8","author":"Cohen","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature25169","article-title":"Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling","volume":"553","author":"Mack","year":"2018","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.ccell.2018.11.001","article-title":"Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia","volume":"34","author":"Ott","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1158\/0008-5472.CAN-18-1888","article-title":"Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition","volume":"79","author":"Hemming","year":"2019","journal-title":"Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1002\/pmic.201300435","article-title":"Posttranslational modifications of human histone H3: An update","volume":"14","author":"Xu","year":"2014","journal-title":"Proteomics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nature09784","article-title":"The Polycomb complex PRC2 and its mark in life","volume":"469","author":"Margueron","year":"2011","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7415","DOI":"10.1093\/nar\/gkr416","article-title":"ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity","volume":"39","author":"Young","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1101\/gr.162008.113","article-title":"Evolution of H3K27me3-marked chromatin is linked to gene expression evolution and to patterns of gene duplication and diversification","volume":"24","author":"Arthur","year":"2014","journal-title":"Genome Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1182\/blood-2014-06-581082","article-title":"Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia","volume":"125","author":"Xu","year":"2015","journal-title":"Blood"},{"key":"ref_96","first-page":"5735","article-title":"EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys(27) acetylation in the BIM gene promoter and enhancers","volume":"14","author":"Huang","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.sbi.2015.09.007","article-title":"Functional coupling between writers, erasers and readers of histone and DNA methylation","volume":"35","author":"Torres","year":"2015","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"a018713","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone acetylation: The histone deacetylase enzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1093\/nar\/gkx1225","article-title":"Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers","volume":"46","author":"Sanchez","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6334","DOI":"10.1093\/nar\/gkx212","article-title":"Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner","volume":"45","author":"Mishra","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/B978-0-12-380866-0.60003-4","article-title":"Histone modifications and cancer","volume":"70","author":"Sawan","year":"2010","journal-title":"Adv. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.cell.2004.12.012","article-title":"Histone demethylation mediated by the nuclear amine oxidase homolog LSD1","volume":"119","author":"Shi","year":"2004","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.bbagrm.2014.03.001","article-title":"Interpreting the language of histone and DNA modifications","volume":"1839","author":"Rothbart","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1016\/j.celrep.2018.03.012","article-title":"Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia","volume":"22","author":"Spencer","year":"2018","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature10805","article-title":"Enhancer decommissioning by LSD1 during embryonic stem cell differentiation","volume":"482","author":"Whyte","year":"2012","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature04020","article-title":"LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription","volume":"437","author":"Metzger","year":"2005","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/nature08839","article-title":"Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4","volume":"464","author":"Metzger","year":"2010","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"19199","DOI":"10.1073\/pnas.0810634105","article-title":"Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules","volume":"105","author":"Hu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.molcel.2009.10.019","article-title":"Progression through the RNA polymerase II CTD cycle","volume":"36","author":"Buratowski","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/nsmb.2912","article-title":"BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones","volume":"21","author":"Kanno","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1139\/bcb-2015-0045","article-title":"RNA polymerase II pausing as a context-dependent reader of the genome","volume":"94","author":"Scheidegger","year":"2016","journal-title":"Biochem. Cell Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bbagrm.2012.11.007","article-title":"Transcription elongation factors DSIF and NELF: Promoter-proximal pausing and beyond","volume":"1829","author":"Yamaguchi","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1146\/annurev-genet-110711-155440","article-title":"Control of transcriptional elongation","volume":"47","author":"Kwak","year":"2013","journal-title":"Ann. Rev. Genet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bbagrm.2010.11.001","article-title":"Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongation","volume":"1809","author":"Nechaev","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"12335","DOI":"10.1074\/jbc.270.21.12335","article-title":"Purification of P-TEFb, a transcription factor required for the transition into productive elongation","volume":"270","author":"Marshall","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.tibs.2015.07.003","article-title":"Ready, pause, go: Regulation of RNA polymerase II pausing and release by cellular signaling pathways","volume":"40","author":"Liu","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.3390\/biom5021063","article-title":"Regulation of transcription elongation and termination","volume":"5","author":"Washburn","year":"2015","journal-title":"Biomolecules"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1101\/gr.152306.112","article-title":"Enhancer transcripts mark active estrogen receptor binding sites","volume":"23","author":"Hah","year":"2013","journal-title":"Genome Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1038\/s41388-018-0150-2","article-title":"The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML","volume":"37","author":"Gerlach","year":"2018","journal-title":"Oncogene"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"84986","DOI":"10.18632\/oncotarget.18583","article-title":"Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors","volume":"8","author":"Moreno","year":"2017","journal-title":"Oncotarget"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13046-018-0704-8","article-title":"CDK9 inhibitors in acute myeloid leukemia","volume":"37","author":"Boffo","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s41591-018-0312-3","article-title":"Small-molecule targeting of brachyury transcription factor addiction in chordoma","volume":"25","author":"Sharifnia","year":"2019","journal-title":"Nature Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/0092-8674(94)90535-5","article-title":"A novel cyclin associates with MO15\/CDK7 to form the CDK-activating kinase","volume":"78","author":"Fisher","year":"1994","journal-title":"Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"6876","DOI":"10.1128\/MCB.23.19.6876-6886.2003","article-title":"Cdk7 is required for full activation of Drosophila heat shock genes and RNA polymerase II phosphorylation in vivo","volume":"23","author":"Schwartz","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1093\/nar\/gkn1061","article-title":"Binding to DNA of the RNA-polymerase II C-terminal domain allows discrimination between Cdk7 and Cdk9 phosphorylation","volume":"37","author":"Lolli","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.molcel.2007.02.003","article-title":"Requirements for Cdk7 in the assembly of Cdk1\/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells","volume":"25","author":"Larochelle","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nature13393","article-title":"Targeting transcription regulation in cancer with a covalent CDK7 inhibitor","volume":"511","author":"Kwiatkowski","year":"2014","journal-title":"Nature"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.cell.2014.10.024","article-title":"CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer","volume":"159","author":"Chipumuro","year":"2014","journal-title":"Cell"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.ccell.2014.10.019","article-title":"Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor","volume":"26","author":"Christensen","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.cell.2015.08.063","article-title":"CDK7-dependent transcriptional addiction in triple-negative breast cancer","volume":"163","author":"Wang","year":"2015","journal-title":"Cell"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1158\/1535-7163.MCT-17-0078","article-title":"Preclinical Efficacy and Molecular Mechanism of Targeting CDK7-Dependent Transcriptional Addiction in Ovarian Cancer","volume":"16","author":"Zhang","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1136\/gutjnl-2016-311818","article-title":"Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma","volume":"66","author":"Jiang","year":"2017","journal-title":"Gut"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.jid.2017.09.056","article-title":"High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma","volume":"138","author":"Eliades","year":"2018","journal-title":"J. Invest. Dermatol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"5747","DOI":"10.2147\/CMAR.S183696","article-title":"CDK7 inhibition is a novel therapeutic strategy against GBM both in vitro and in vivo","volume":"10","author":"Meng","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Lu, P., Geng, J., Zhang, L., Wang, Y., Niu, N., Fang, Y., Liu, F., Shi, J., Zhang, Z.G., and Sun, Y.W. (2019). THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer. Oncogene.","DOI":"10.1038\/s41388-019-0701-1"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Lu, L., Jiang, G., Chen, Z., Li, J., An, P., Chen, L., Du, J., and Wang, H. (2018). Targeting CDK7 increases the stability of Snail to promote the dissemination of colorectal cancer. Cell Death Differ.","DOI":"10.1038\/s41418-018-0222-4"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.molcel.2015.06.032","article-title":"THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing","volume":"59","author":"Nilson","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Sampathi, S., Acharya, P., Zhao, Y., Wang, J., Stengel, K.R., Liu, Q., Savona, M.R., and Hiebert, S.W. (2019). The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5\u2032 and 3\u2032 ends of genes. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkz127"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Olson, C.M., Liang, Y., Leggett, A., Park, W.D., Li, L., Mills, C.E., Elsarrag, S.Z., Ficarro, S.B., Zhang, T., and Duster, R. (2019). Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype. Cell Chem. Biol.","DOI":"10.1016\/j.chembiol.2019.02.012"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.tibs.2005.03.011","article-title":"Mediator and the mechanism of transcriptional activation","volume":"30","author":"Kornberg","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"575","DOI":"10.3109\/10409238.2013.840259","article-title":"The Mediator complex and transcription regulation","volume":"48","author":"Poss","year":"2013","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrm3951","article-title":"The Mediator complex: A central integrator of transcription","volume":"16","author":"Allen","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/nature09380","article-title":"Mediator and cohesin connect gene expression and chromatin architecture","volume":"467","author":"Kagey","year":"2010","journal-title":"Nature"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1073\/pnas.81.16.5017","article-title":"An operator at -280 base pairs that is required for repression of araBAD operon promoter: Addition of DNA helical turns between the operator and promoter cyclically hinders repression","volume":"81","author":"Dunn","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nature06634","article-title":"Cohesin mediates transcriptional insulation by CCCTC-binding factor","volume":"451","author":"Wendt","year":"2008","journal-title":"Nature"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0092-8674(00)81967-4","article-title":"The protein CTCF is required for the enhancer blocking activity of vertebrate insulators","volume":"98","author":"Bell","year":"1999","journal-title":"Cell"},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhang, Z., Bando, M., Itoh, T., Deardorff, M.A., Clark, D., Kaur, M., Tandy, S., Kondoh, T., and Rappaport, E. (2009). Transcriptional dysregulation in NIPBL and cohesin mutant human cells. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000119"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1242\/jcs.00734","article-title":"The mediator coactivator complex: Functional and physical roles in transcriptional regulation","volume":"116","author":"Lewis","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.molcel.2016.09.015","article-title":"Mediator Undergoes a Compositional Change during Transcriptional Activation","volume":"64","author":"Petrenko","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nature14904","article-title":"Mediator kinase inhibition further activates super-enhancer-associated genes in AML","volume":"526","author":"Pelish","year":"2015","journal-title":"Nature"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.cell.2013.04.048","article-title":"HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia","volume":"153","author":"Galbraith","year":"2013","journal-title":"Cell"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature07179","article-title":"CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity","volume":"455","author":"Firestein","year":"2008","journal-title":"Nature"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.celrep.2018.02.011","article-title":"Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer","volume":"22","author":"Pawar","year":"2018","journal-title":"Cell Rep."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"9489","DOI":"10.1038\/srep09489","article-title":"GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1","volume":"5","author":"Kumar","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature14888","article-title":"BET inhibitor resistance emerges from leukaemia stem cells","volume":"525","author":"Fong","year":"2015","journal-title":"Nature"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nature14898","article-title":"Transcriptional plasticity promotes primary and acquired resistance to BET inhibition","volume":"525","author":"Rathert","year":"2015","journal-title":"Nature"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1158\/1078-0432.CCR-16-0453","article-title":"The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer","volume":"23","author":"Ma","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Ambrosini, G., Do, C., Tycko, B., Realubit, R.B., Karan, C., Musi, E., Carvajal, R.D., Chua, V., Aplin, A.E., and Schwartz, G.K. (2019). Inhibition of NF-kappaB-dependent signaling enhances sensitivity and overcomes resistance to BET inhibition in uveal melanoma. Cancer Res.","DOI":"10.1158\/0008-5472.CAN-18-3177"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1016\/j.celrep.2018.12.016","article-title":"Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma","volume":"25","author":"Fulciniti","year":"2018","journal-title":"Cell Rep."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature11606","article-title":"EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations","volume":"492","author":"McCabe","year":"2012","journal-title":"Nature"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nm.4036","article-title":"Targeting EZH2 in cancer","volume":"22","author":"Kim","year":"2016","journal-title":"Nature Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/356713a0","article-title":"Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients","volume":"356","author":"Basu","year":"1992","journal-title":"Nature"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ng.3095","article-title":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors","volume":"46","author":"Lee","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"14992","DOI":"10.1038\/s41598-017-15183-1","article-title":"The genomic landscape of malignant peripheral nerve sheath tumors: Diverse drivers of Ras pathway activation","volume":"7","author":"Brohl","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.oraloncology.2012.05.024","article-title":"Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent\/metastatic head and neck cancer","volume":"48","author":"Haigentz","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"7138","DOI":"10.1158\/1078-0432.CCR-08-0122","article-title":"A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: A California Cancer Consortium study","volume":"14","author":"Luu","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ygyno.2008.01.009","article-title":"A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study","volume":"109","author":"Modesitt","year":"2008","journal-title":"Gynecol. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00280-017-3494-3","article-title":"Phase I\/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors","volume":"81","author":"Chan","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Teknos, T.N., Grecula, J., Agrawal, A., Old, M.O., Ozer, E., Carrau, R., Kang, S., Rocco, J., Blakaj, D., and Diavolitsis, V. (2018). A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma. Invest. New Drugs.","DOI":"10.1007\/s10637-018-0696-4"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/bjc.2017.33","article-title":"Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: A multicentre, single-arm phase I\/II clinical trial","volume":"116","author":"Pili","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature09033","article-title":"Widespread transcription at neuronal activity-regulated enhancers","volume":"465","author":"Kim","year":"2010","journal-title":"Nature"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.molcel.2014.08.023","article-title":"Enhancer RNA facilitates NELF release from immediate early genes","volume":"56","author":"Schaukowitch","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"14121","DOI":"10.1073\/pnas.1616697113","article-title":"Epstein\u2013Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation","volume":"113","author":"Liang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.1073\/pnas.1414841112","article-title":"RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin alpha-subunit gene","volume":"112","author":"Pnueli","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"e00179","DOI":"10.1042\/BSR20140126","article-title":"Chromatin looping and eRNA transcription precede the transcriptional activation of gene in the \u03b2-globin locus","volume":"35","author":"Kim","year":"2015","journal-title":"Biosci. Rep."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"12648","DOI":"10.1038\/srep12648","article-title":"Genome-wide analysis of enhancer RNA in gene regulation across 12 mouse tissues","volume":"5","author":"Cheng","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1172\/JCI83265","article-title":"CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer","volume":"126","author":"McCleland","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.celrep.2016.03.038","article-title":"Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer","volume":"15","author":"Zhao","year":"2016","journal-title":"Cell Rep."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1158\/0008-5472.CAN-15-0484","article-title":"Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers","volume":"76","author":"Kaczkowski","year":"2016","journal-title":"Cancer Res."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1126\/science.1162228","article-title":"Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters","volume":"322","author":"Core","year":"2008","journal-title":"Science"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1126\/science.aad9841","article-title":"TT-seq maps the human transient transcriptome","volume":"352","author":"Schwalb","year":"2016","journal-title":"Science"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1038\/nprot.2016.086","article-title":"Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq)","volume":"11","author":"Mahat","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1038\/s41588-018-0244-3","article-title":"Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme","volume":"50","author":"Chu","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1073\/pnas.75.1.285","article-title":"Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide","volume":"75","author":"Stephenson","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature11362","article-title":"Targeting nuclear RNA for in vivo correction of myotonic dystrophy","volume":"488","author":"Wheeler","year":"2012","journal-title":"Nature"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"17921","DOI":"10.1073\/pnas.1317023110","article-title":"Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants","volume":"110","author":"Parker","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13072-015-0015-7","article-title":"Motif signatures in stretch enhancers are enriched for disease-associated genetic variants","volume":"8","author":"Quang","year":"2015","journal-title":"Epigenetics Chromatin"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1080\/15592294.2018.1514231","article-title":"Super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers","volume":"13","author":"Khan","year":"2018","journal-title":"Epigenetics"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1160631","article-title":"Shadow enhancers as a source of evolutionary novelty","volume":"321","author":"Hong","year":"2008","journal-title":"Science"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1101\/gad.294744.116","article-title":"SET1A\/COMPASS and shadow enhancers in the regulation of homeotic gene expression","volume":"31","author":"Cao","year":"2017","journal-title":"Genes Dev."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1101\/sqb.2015.80.027268","article-title":"Regulatory Domains and Their Mechanisms","volume":"80","author":"Benabdallah","year":"2015","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1126\/science.1067799","article-title":"Capturing chromosome conformation","volume":"295","author":"Dekker","year":"2002","journal-title":"Science"},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"van Berkum, N.L., Lieberman-Aiden, E., Williams, L., Imakaev, M., Gnirke, A., Mirny, L.A., Dekker, J., and Lander, E.S. (2010). Hi-C: A method to study the three-dimensional architecture of genomes. J. Vis. Exp.","DOI":"10.3791\/1869-v"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nature08497","article-title":"An oestrogen-receptor-alpha-bound human chromatin interactome","volume":"462","author":"Fullwood","year":"2009","journal-title":"Nature"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/nmeth.3999","article-title":"HiChIP: Efficient and sensitive analysis of protein-directed genome architecture","volume":"13","author":"Mumbach","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1093\/nar\/gkw036","article-title":"\u0394Np63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma","volume":"44","author":"Bretz","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1111\/cas.13394","article-title":"Elevated expression of DeltaNp63 in advanced esophageal squamous cell carcinoma","volume":"108","author":"Kumakura","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s00428-018-2324-2","article-title":"p63 isoforms in triple-negative breast cancer: DeltaNp63 associates with the basal phenotype whereas TAp63 associates with androgen receptor, lack of BRCA mutation, PTEN and improved survival","volume":"472","author":"Coates","year":"2018","journal-title":"Virchows Arch."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"10133","DOI":"10.1007\/s13277-016-4880-x","article-title":"DeltaNp63 regulates cell proliferation, differentiation, adhesion, and migration in the BL2 subtype of basal-like breast cancer","volume":"37","author":"Orzol","year":"2016","journal-title":"Tumour Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/5\/634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:49:38Z","timestamp":1760186978000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/5\/634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,7]]},"references-count":200,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["cancers11050634"],"URL":"https:\/\/doi.org\/10.3390\/cancers11050634","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201903.0288.v1","asserted-by":"object"}]},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,7]]}}}