{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T10:05:52Z","timestamp":1774605952536,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Esophageal cancer (EC) is the seventh most common cancer worldwide and the sixth leading cause of death, according to Globocan 2018. Despite efforts made for therapeutic advances, EC remains highly lethal, portending a five-year overall survival of just 15\u201320%. Hence, the discovery of new molecular targets that might improve therapeutic efficacy is urgently needed. Due to high proliferative rates and also the limited oxygen and nutrient diffusion in tumors, the development of hypoxic regions and consequent activation of hypoxia-inducible factors (HIFs) are a common characteristic of solid tumors, including EC. Accordingly, HIF-1\u03b1, involved in cell cycle deregulation, apoptosis, angiogenesis induction and proliferation in cancer, constitutes a predictive marker of resistance to radiotherapy (RT). Deregulation of epigenetic mechanisms, including aberrant DNA methylation and histone modifications, have emerged as critical factors in cancer development and progression. Recently, interactions between epigenetic enzymes and HIF-1\u03b1 transcription factors have been reported. Thus, further insight into hypoxia-induced epigenetic alterations in EC may allow the identification of novel therapeutic targets and predictive biomarkers, impacting on patient survival and quality of life.<\/jats:p>","DOI":"10.3390\/genes10110927","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T10:56:34Z","timestamp":1573728994000},"page":"927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7434-8398","authenticated-orcid":false,"given":"Catarina","family":"Macedo-Silva","sequence":"first","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center at Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]},{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center at Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center at Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology at Portuguese Oncology Institute of Porto (CI-IPOP), Portugal, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology at Institute of Biomedical Sciences Abel Salazar\u2014University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center at Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology at Institute of Biomedical Sciences Abel Salazar\u2014University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"Isabel","family":"Bravo","sequence":"additional","affiliation":[{"name":"Medical Physics, Radiobiology and Radiation Protection Group\u2014Research Center at Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3322\/caac.21349","article-title":"Cancer treatment and survivorship statistics, 2016","volume":"66","author":"Miller","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4251\/wjgo.v6.i5.112","article-title":"Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities","volume":"6","author":"Napier","year":"2014","journal-title":"World. J. Gastrointest. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1136\/gutjnl-2014-308124","article-title":"Global incidence of oesophageal cancer by histological subtype in 2012","volume":"64","author":"Arnold","year":"2015","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S1367","DOI":"10.1016\/S0003-4975(03)01202-5","article-title":"Geographical distribution and racial disparity in esophageal cancer","volume":"76","author":"Pickens","year":"2003","journal-title":"Ann. Thorac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1093\/jnci\/djg047","article-title":"Population attributable risks of esophageal and gastric cancers","volume":"95","author":"Engel","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.4251\/wjgo.v6.i10.403","article-title":"Neoadjuvant therapy for esophageal cancer","volume":"6","author":"Shah","year":"2014","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.3748\/wjg.v16.i30.3793","article-title":"Neoadjuvant treatment of esophageal cancer","volume":"16","author":"Campbell","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1097\/COC.0b013e3181e841ce","article-title":"Outcomes after trimodality therapy for esophageal cancer: The impact of histology on failure patterns","volume":"34","author":"Koshy","year":"2011","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.21037\/acs.2017.02.01","article-title":"Future directions in esophageal cancer therapy","volume":"6","author":"Wald","year":"2017","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1200\/EDBK_158808","article-title":"Tumor Heterogeneity and Therapeutic Resistance","volume":"35","author":"Lovly","year":"2016","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ymeth.2017.07.002","article-title":"Hypoxia and hypoxia response-associated molecular markers in esophageal cancer: A systematic review","volume":"130","author":"Peerlings","year":"2017","journal-title":"Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.bbabio.2017.02.001","article-title":"Cancer metabolism in space and time: Beyond the Warburg effect","volume":"1858","author":"Danhier","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.pharmthera.2017.02.011","article-title":"Epigenetics in cancer: Fundamentals and Beyond","volume":"173","author":"Biswas","year":"2017","journal-title":"Pharmacol. Therapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng1089","article-title":"Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals","volume":"33","author":"Jaenisch","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s12272-013-0058-x","article-title":"Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics","volume":"36","author":"Nguyen","year":"2013","journal-title":"Arch. Pharmacal Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chi, H.C., Tsai, C.Y., Tsai, M.M., and Lin, K.H. (2018). Impact of DNA and RNA Methylation on Radiobiology and Cancer Progression. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020555"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.radonc.2014.05.001","article-title":"Epigenetics in radiotherapy: Where are we heading?","volume":"111","author":"Smits","year":"2014","journal-title":"Radiolther. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2147\/CMAR.S144687","article-title":"Radiotherapy for esophageal carcinoma: Dose, response and survival","volume":"10","author":"Luo","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fmolb.2014.00024","article-title":"Biological response of cancer cells to radiation treatment","volume":"1","author":"Baskar","year":"2014","journal-title":"Front. Mol. Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.clon.2007.04.009","article-title":"Molecular biology for the radiation oncologist: The 5Rs of radiobiology meet the hallmarks of cancer","volume":"19","author":"Harrington","year":"2007","journal-title":"Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.clon.2013.06.007","article-title":"Biological consequences of radiation-induced DNA damage: Relevance to radiotherapy","volume":"25","author":"Lomax","year":"2013","journal-title":"Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.ijrobp.2004.03.005","article-title":"Role of cell cycle in mediating sensitivity to radiotherapy","volume":"59","author":"Pawlik","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.3892\/ol.2014.1990","article-title":"Repopulation of tumor cells during fractionated radiotherapy and detection methods (Review)","volume":"7","author":"Yang","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2147\/HP.S93413","article-title":"The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy","volume":"3","author":"Muz","year":"2015","journal-title":"Hypoxia"},{"key":"ref_27","unstructured":"Hall, E.J., and Giaccia, A.J. (2012). Radiobiology for the Radiologist, Wolters Kluwer Health\/Lippincott Williams & Wilkins. [7th ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00795-017-0171-x","article-title":"Clinically relevant radioresistant cell line: A simple model to understand cancer radioresistance","volume":"50","author":"Kuwahara","year":"2017","journal-title":"Med. Mol. Morphol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.gendis.2016.11.003","article-title":"The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism","volume":"4","author":"Lv","year":"2017","journal-title":"Genes. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fcell.2019.00004","article-title":"Hypoxia-Modified Cancer Cell Metabolism","volume":"7","author":"Dale","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10555-007-9063-1","article-title":"Hypoxia, gene expression, and metastasis","volume":"26","author":"Chan","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Martin, J.D., Fukumura, D., Duda, D.G., Boucher, Y., and Jain, R.K. (2016). Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity. Cold Spring Harb. Perspect. Med., 6.","DOI":"10.1101\/cshperspect.a031195"},{"key":"ref_33","first-page":"1830","article-title":"Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy","volume":"61","author":"Koukourakis","year":"2001","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1010428317717983","DOI":"10.1177\/1010428317717983","article-title":"Expression of hypoxia inducible factor 1 alpha and its clinical significance in esophageal carcinoma: A meta-analysis","volume":"39","author":"Jing","year":"2017","journal-title":"Tumour Biol."},{"key":"ref_35","first-page":"2351","article-title":"Clinical significance of HIF-1alpha expression in patients with esophageal cancer treated with concurrent chemoradiotherapy","volume":"31","author":"Ogawa","year":"2011","journal-title":"Anticancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1349-7006.2005.00025.x","article-title":"Expression of hypoxia-inducible factor-1alpha in esophageal squamous cell carcinoma","volume":"96","author":"Matsuyama","year":"2005","journal-title":"Cancer Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrc1367","article-title":"Exploiting tumour hypoxia in cancer treatment","volume":"4","author":"Brown","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.4161\/cbt.26426","article-title":"Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1alpha in vitro and in vivo","volume":"14","author":"Yang","year":"2013","journal-title":"Cancer Biol."},{"key":"ref_39","first-page":"3369","article-title":"Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells","volume":"31","author":"Kato","year":"2011","journal-title":"Anticancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"442","DOI":"10.2174\/156652409788167087","article-title":"Hypoxia and radiation therapy: Past history, ongoing research, and future promise","volume":"9","author":"Rockwell","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/carcin\/bgp220","article-title":"Epigenetics in cancer","volume":"31","author":"Sharma","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jnutbio.2005.05.003","article-title":"Lysine residues in N-terminal and C-terminal regions of human histone H2A are targets for biotinylation by biotinidase","volume":"17","author":"Chew","year":"2006","journal-title":"J. Nutr. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2007.02.005","article-title":"Chromatin modifications and their function","volume":"128","author":"Kouzarides","year":"2007","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1038\/onc.2011.121","article-title":"Histone onco-modifications","volume":"30","author":"Fullgrabe","year":"2011","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"R546","DOI":"10.1016\/j.cub.2004.07.007","article-title":"Histones and histone modifications","volume":"14","author":"Peterson","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.bbagrm.2014.05.009","article-title":"Targeting histone lysine demethylases - progress, challenges, and the future","volume":"1839","author":"Thinnes","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nrg2218","article-title":"Histone lysine demethylases: Emerging roles in development, physiology and disease","volume":"8","author":"Shi","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.molcel.2012.11.006","article-title":"Histone lysine methylation dynamics: Establishment, regulation, and biological impact","volume":"48","author":"Black","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_50","first-page":"34","article-title":"Histone demethylases and their roles in cancer epigenetics","volume":"1","author":"Tian","year":"2016","journal-title":"J. Med. Oncol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6623","DOI":"10.1002\/jcb.26841","article-title":"Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90","volume":"119","author":"Tao","year":"2018","journal-title":"J Cell. Biochem."},{"key":"ref_52","first-page":"333","article-title":"Histone H4 acetylation and histone deacetylase 1 expression in esophageal squamous cell carcinoma","volume":"10","author":"Toh","year":"2003","journal-title":"Oncol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.3892\/or.2014.3307","article-title":"Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma","volume":"32","author":"Dong","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_54","first-page":"509","article-title":"Histone demethylase GASC1, a potential prognostic and predictive marker in esophageal squamous cell carcinoma","volume":"3","author":"Sun","year":"2013","journal-title":"Am. J. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sun, X., Qiu, J.J., Zhu, S., Cao, B., Sun, L., Li, S., Li, P., Zhang, S., and Dong, S. (2013). Oncogenic features of PHF8 histone demethylase in esophageal squamous cell carcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077353"},{"key":"ref_56","first-page":"115","article-title":"Histone demethylase JMJD1C regulates esophageal cancer proliferation Via YAP1 signaling","volume":"7","author":"Cai","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/ijc.29714","article-title":"Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer","volume":"138","author":"Kosumi","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.bbrc.2013.05.123","article-title":"High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma","volume":"437","author":"Yu","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","article-title":"DNA methylation and cancer","volume":"70","author":"Kulis","year":"2010","journal-title":"Adv. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"48644","DOI":"10.18632\/oncotarget.8777","article-title":"Emerging therapeutic targets in esophageal adenocarcinoma","volume":"7","author":"Gaur","year":"2016","journal-title":"Oncotarget"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.canlet.2012.02.036","article-title":"Epigenetic biomarkers in esophageal cancer","volume":"342","author":"Kaz","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4705","DOI":"10.3390\/ijms12074705","article-title":"Epigenetics: New questions on the response to hypoxia","volume":"12","author":"Acevedo","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/ijc.28190","article-title":"Epigenetic regulation of hypoxia-responsive gene expression: Focusing on chromatin and DNA modifications","volume":"134","author":"Tsai","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"547","DOI":"10.4161\/epi.5.6.12400","article-title":"Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells","volume":"5","author":"Skowronski","year":"2010","journal-title":"Epigenetics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7603\/s40681-016-0001-9","article-title":"Epigenetics, TET proteins, and hypoxia in epithelial-mesenchymal transition and tumorigenesis","volume":"6","author":"Chen","year":"2016","journal-title":"Biomedicine"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13059-014-0513-0","article-title":"TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator","volume":"15","author":"Tsai","year":"2014","journal-title":"Genome Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/86507","article-title":"Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes","volume":"7","author":"Kim","year":"2001","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.bbrc.2012.04.143","article-title":"Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysine demethylases","volume":"422","author":"Vavilala","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"180","DOI":"10.14336\/AD.2015.0929","article-title":"Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases","volume":"7","author":"Salminen","year":"2016","journal-title":"Aging Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"791","DOI":"10.2217\/epi.15.24","article-title":"Epigenetic regulation by histone demethylases in hypoxia","volume":"7","author":"Hancock","year":"2015","journal-title":"Epigenomics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1182\/bloodadvances.2017008847","article-title":"Hypoxia-inducible KDM3A addiction in multiple myeloma","volume":"2","author":"Ikeda","year":"2018","journal-title":"Blood Adv."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"E7212","DOI":"10.1073\/pnas.1612626113","article-title":"HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia","volume":"113","author":"Chakraborty","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1158\/0008-5472.CAN-12-3231","article-title":"Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages","volume":"73","author":"Osawa","year":"2013","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E3367","DOI":"10.1073\/pnas.1217394109","article-title":"Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression","volume":"109","author":"Luo","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1158\/0008-5472.CAN-12-4300","article-title":"KDM4\/JMJD2 histone demethylases: Epigenetic regulators in cancer cells","volume":"73","author":"Berry","year":"2013","journal-title":"Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"43","DOI":"10.14348\/molcells.2014.2250","article-title":"HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions","volume":"37","author":"Lee","year":"2014","journal-title":"Mol. Cells"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/abbs\/gmu122","article-title":"Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2alpha","volume":"47","author":"Guo","year":"2015","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1080\/15592294.2015.1039216","article-title":"Selective inhibition of esophageal cancer cells by combination of HDAC inhibitors and Azacytidine","volume":"10","author":"Ahrens","year":"2015","journal-title":"Epigenetics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"36542","DOI":"10.1074\/jbc.M804578200","article-title":"The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF","volume":"283","author":"Beyer","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1002\/cam4.1614","article-title":"The pivotal role of DNA methylation in the radio-sensitivity of tumor radiotherapy","volume":"7","author":"Zhu","year":"2018","journal-title":"Cancer Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1080\/09553002.2017.1287454","article-title":"Effects of ionizing radiation on DNA methylation: From experimental biology to clinical applications","volume":"93","author":"Miousse","year":"2017","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cgh.2006.03.007","article-title":"Promoter methylation and response to chemotherapy and radiation in esophageal cancer","volume":"4","author":"Hamilton","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5927","DOI":"10.1038\/sj.onc.1210403","article-title":"Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis","volume":"26","author":"Sakakura","year":"2007","journal-title":"Oncogene"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1748-717X-9-15","article-title":"Radiation-induced alterations of histone post-translational modification levels in lymphoblastoid cell lines","volume":"9","author":"Maroschik","year":"2014","journal-title":"Radiat. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"52823","DOI":"10.18632\/oncotarget.17275","article-title":"Chromatin remodeling modulates radiosensitivity of the daughter cells derived from cell population exposed to low- and high-LET irradiation","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1146\/annurev-med-111314-035900","article-title":"Epigenetic Therapeutics: A New Weapon in the War Against Cancer","volume":"67","author":"Ahuja","year":"2016","journal-title":"Annu. Rev. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"15059","DOI":"10.3390\/ijms140715059","article-title":"Epigenetics meets radiation biology as a new approach in cancer treatment","volume":"14","author":"Kim","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3389\/fonc.2014.00080","article-title":"DNA methyltransferases: A novel target for prevention and therapy","volume":"4","author":"Subramaniam","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Oronsky, B., Scicinski, J., Kim, M.M., Cabrales, P., Salacz, M.E., Carter, C.A., Oronsky, N., Lybeck, H., Lybeck, M., and Larson, C. (2016). Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents. Biomolecules, 6.","DOI":"10.3390\/biom6030032"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/bjc.2016.278","article-title":"Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition","volume":"115","author":"Jonsson","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3892\/or.2015.4089","article-title":"Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells","volume":"34","author":"Makita","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1074\/jbc.M600456200","article-title":"Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha","volume":"281","author":"Fath","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Chen, S.Y., and Sang, N.L. (2011). Histone Deacetylase Inhibitors: The Epigenetic Therapeutics That Repress Hypoxia-Inducible Factors. J. Biomed. Biotechnol., 2011.","DOI":"10.1155\/2011\/197946"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2217\/epi.15.115","article-title":"Inhibiting the Jumonji family: A potential new clinical approach to targeting aberrant epigenetic mechanisms","volume":"8","author":"Martinez","year":"2016","journal-title":"Epigenomics"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"34896","DOI":"10.18632\/oncotarget.16820","article-title":"Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells","volume":"8","author":"Banelli","year":"2017","journal-title":"Oncotarget"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1021\/acsmedchemlett.7b00220","article-title":"Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models","volume":"8","author":"Chen","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.coph.2015.05.009","article-title":"Advances in the development of histone lysine demethylase inhibitors","volume":"23","author":"Maes","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.celrep.2018.09.081","article-title":"Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks","volume":"25","author":"Bayo","year":"2018","journal-title":"Cell Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1158\/1535-7163.MCT-17-1053","article-title":"Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity","volume":"17","author":"Rath","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Pippa, S., Mannironi, C., Licursi, V., Bombardi, L., Colotti, G., Cundari, E., Mollica, A., Coluccia, A., Naccarato, V., and La Regina, G. (2019). Small Molecule Inhibitors of KDM5 Histone Demethylases Increase Radio-Sensitivity of Breast Cancer Cells Over-Expressing JARID1B. Molecules, 24.","DOI":"10.20944\/preprints201806.0131.v1"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/927\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:34:27Z","timestamp":1760189667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":100,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["genes10110927"],"URL":"https:\/\/doi.org\/10.3390\/genes10110927","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]}}}