{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:13:59Z","timestamp":1790180039846,"version":"4.1.0"},"reference-count":53,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:p>We show that HEXIM1 (hexamethylene bis-acetamide inducible 1) functions as an AR (androgen receptor) co-repressor as it physically interacts with the AR and is required for the ability of anti-androgens to inhibit androgen-induced target gene expression and cell proliferation. Oncomine\u2122 database and IHC (immunohistochemistry) analyses of human prostate tissues revealed that expression of HEXIM1 mRNA and protein are down-regulated during the development and progression of prostate cancer. Enforced down-regulation of HEXIM1\u00a0in parental hormone-dependent LNCaP cells results in resistance to the inhibitory action of anti-androgens. Conversely, ectopic expression of HEXIM1\u00a0in the CRPC (castration-resistant prostate cancer) cell line, C4-2, enhances their sensitivity to the repressive effects of the anti-androgen bicalutamide. Novel insight into the mechanistic basis for HEXIM1 inhibition of AR activity is provided by the present studies showing that HEXIM1 induces expression of the histone demethylase KDM5B (lysine-specific demethylase 5B) and inhibits histone methylation, resulting in the inhibition of FOXA1 (forkhead box A1) licensing activity. This is a new mechanism of action attributed to HEXIM1, and distinct from what has been reported so far to be involved in HEXIM1 regulation of other nuclear hormone receptors, including the oestrogen receptor.<\/jats:p>","DOI":"10.1042\/bj20140174","type":"journal-article","created":{"date-parts":[[2014,5,21]],"date-time":"2014-05-21T08:35:14Z","timestamp":1400661314000},"page":"315-327","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens"],"prefix":"10.1042","volume":"462","author":[{"given":"I-Ju","family":"Yeh","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung","family":"Song","sequence":"additional","affiliation":[{"name":"Division of General Medical Science\u2013Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan\u00a0M.","family":"Wittmann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Bai","sequence":"additional","affiliation":[{"name":"Center for RNA Biology, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Danielpour","sequence":"additional","affiliation":[{"name":"Division of General Medical Science\u2013Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica\u00a0M.","family":"Montano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2014,8,7]]},"reference":[{"key":"2021112216050134900_B1","doi-asserted-by":"publisher","first-page":"2855","DOI":"10.1210\/me.2007-0223","article-title":"Androgen receptor structural and functional elements: role and regulation in prostate cancer","volume":"21","author":"Dehm","year":"2007","journal-title":"Mol. Endocrinol."},{"key":"2021112216050134900_B2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.canlet.2008.06.007","article-title":"Progression of prostate cancer: multiple pathways to androgen independence","volume":"274","author":"Devlin","year":"2009","journal-title":"Cancer Lett."},{"key":"2021112216050134900_B3","doi-asserted-by":"publisher","first-page":"5576","DOI":"10.1038\/sj.onc.1208728","article-title":"The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1","volume":"24","author":"Wittmann","year":"2005","journal-title":"Oncogene"},{"key":"2021112216050134900_B4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.gene.2004.05.007","article-title":"Cellular control of gene expression by T-type cyclin\/CDK9 complexes","volume":"337","author":"Garriga","year":"2004","journal-title":"Gene"},{"key":"2021112216050134900_B5","doi-asserted-by":"publisher","first-page":"7015","DOI":"10.1158\/0008-5472.CAN-08-0814","article-title":"HEXIM1 regulates E2\/ER\u03b1-mediated expression of cyclin D1\u00a0in mammary cells via modulation of P-TEFb","volume":"68","author":"Ogba","year":"2008","journal-title":"Cancer Res."},{"key":"2021112216050134900_B6","doi-asserted-by":"publisher","first-page":"3639","DOI":"10.1038\/onc.2010.110","article-title":"HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland","volume":"29","author":"Ogba","year":"2010","journal-title":"Oncogene"},{"key":"2021112216050134900_B7","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.cell.2009.04.056","article-title":"Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer","volume":"138","author":"Wang","year":"2009","journal-title":"Cell"},{"key":"2021112216050134900_B8","first-page":"2577","article-title":"Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer","volume":"54","author":"Thalmann","year":"1994","journal-title":"Cancer Res."},{"key":"2021112216050134900_B9","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1210\/me.2010-0165","article-title":"DHT selectively reverses Smad3-mediated\/TGF-\u03b2-induced responses through transcriptional down-regulation of Smad3\u00a0in prostate epithelial cells","volume":"24","author":"Song","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"2021112216050134900_B10","doi-asserted-by":"publisher","first-page":"6947","DOI":"10.1073\/pnas.96.12.6947","article-title":"An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens","volume":"96","author":"Montano","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112216050134900_B11","first-page":"5151","article-title":"Identification of a novel inhibitor of cell growth that is down-regulated by estrogens and decreased in breast tumors","volume":"63","author":"Wittmann","year":"2003","journal-title":"Cancer Res."},{"key":"2021112216050134900_B12","doi-asserted-by":"publisher","first-page":"3563","DOI":"10.1038\/onc.2011.76","article-title":"HEXIM1 is a critical determinant of the response to tamoxifen","volume":"30","author":"Ketchart","year":"2011","journal-title":"Oncogene"},{"key":"2021112216050134900_B13","doi-asserted-by":"publisher","first-page":"3829","DOI":"10.1038\/onc.2012.405","article-title":"Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis","volume":"32","author":"Ketchart","year":"2013","journal-title":"Oncogene"},{"key":"2021112216050134900_B14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1161\/CIRCRESAHA.107.157859","article-title":"Mutation of the HEXIM1 gene results in defects during heart and vascular development partly through downregulation of vascular endothelial growth factor","volume":"102","author":"Montano","year":"2008","journal-title":"Circ. Res."},{"key":"2021112216050134900_B15","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1002\/cncr.23304","article-title":"Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect","volume":"112","author":"Ross","year":"2008","journal-title":"Cancer"},{"key":"2021112216050134900_B16","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1111\/j.2047-2927.2013.00068.x","article-title":"Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy","volume":"1","author":"Shibata","year":"2013","journal-title":"Andrology"},{"key":"2021112216050134900_B17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/ng1935","article-title":"Integrative molecular concept modeling of prostate cancer progression","volume":"39","author":"Tomlins","year":"2007","journal-title":"Nat. Genet."},{"key":"2021112216050134900_B18","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.ccr.2005.10.001","article-title":"Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression","volume":"8","author":"Varambally","year":"2005","journal-title":"Cancer Cell."},{"key":"2021112216050134900_B19","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.1200\/JCO.2004.05.158","article-title":"Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy","volume":"22","author":"Yu","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"2021112216050134900_B20","doi-asserted-by":"publisher","first-page":"19226","DOI":"10.1073\/pnas.0700735104","article-title":"JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer","volume":"104","author":"Xiang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112216050134900_B21","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1101\/gad.621811","article-title":"Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation","volume":"25","author":"Vicent","year":"2011","journal-title":"Genes Dev."},{"key":"2021112216050134900_B22","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1038\/emboj.2011.154","article-title":"Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth","volume":"30","author":"Chen","year":"2011","journal-title":"EMBO J."},{"key":"2021112216050134900_B23","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1210\/jc.2011-2353","article-title":"Androgen deprivation therapy as primary treatment for prostate cancer","volume":"97","author":"Cannata","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021112216050134900_B24","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1111\/j.1742-1241.2011.02799.x","article-title":"Characterising the castration-resistant prostate cancer population: a systematic review","volume":"65","author":"Kirby","year":"2011","journal-title":"Int. J. Clin. Pract."},{"key":"2021112216050134900_B25","doi-asserted-by":"publisher","first-page":"870","DOI":"10.2174\/156800911796798904","article-title":"Androgen receptor cofactors in prostate cancer: potential therapeutic targets of castration-resistant prostate cancer","volume":"11","author":"Shiota","year":"2011","journal-title":"Curr. Cancer Drug Targets"},{"key":"2021112216050134900_B26","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s12672-010-0044-4","article-title":"Androgen action in prostate cancer","volume":"1","author":"Basu","year":"2010","journal-title":"Horm. Cancer"},{"key":"2021112216050134900_B27","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/pros.21038","article-title":"Global levels of histone modifications predict prostate cancer recurrence","volume":"70","author":"Ellinger","year":"2010","journal-title":"Prostate"},{"key":"2021112216050134900_B28","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0960-0760(03)00005-0","article-title":"Molecular communication between androgen receptor and general transcription machinery","volume":"84","author":"Lee","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"2021112216050134900_B29","doi-asserted-by":"publisher","first-page":"9978","DOI":"10.1074\/jbc.M002285200","article-title":"Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation","volume":"276","author":"Lee","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112216050134900_B30","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/S1097-2765(03)00388-5","article-title":"Inhibition of P-TEFb (CDK9\/cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA","volume":"12","author":"Yik","year":"2003","journal-title":"Mol. Cell"},{"key":"2021112216050134900_B31","doi-asserted-by":"publisher","first-page":"2608","DOI":"10.1038\/sj.emboj.7600275","article-title":"Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9\/cyclin T) inhibitor","volume":"23","author":"Michels","year":"2004","journal-title":"EMBO J."},{"key":"2021112216050134900_B32","doi-asserted-by":"publisher","first-page":"16360","DOI":"10.1074\/jbc.M500424200","article-title":"HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK","volume":"180","author":"Byers","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112216050134900_B33","doi-asserted-by":"publisher","first-page":"28819","DOI":"10.1074\/jbc.M502712200","article-title":"Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186","volume":"280","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112216050134900_B34","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.cell.2005.04.031","article-title":"Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF","volume":"121","author":"Dou","year":"2005","journal-title":"Cell"},{"key":"2021112216050134900_B35","doi-asserted-by":"publisher","first-page":"4198","DOI":"10.1038\/emboj.2011.295","article-title":"H3K4 tri-methylation provides an epigenetic signature of active enhancers","volume":"30","author":"Pekowska","year":"2011","journal-title":"EMBO J."},{"key":"2021112216050134900_B36","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/embor.2009.108","article-title":"CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3\u2032-end processing","volume":"10","author":"Pirngruber","year":"2009","journal-title":"EMBO Rep."},{"key":"2021112216050134900_B37","doi-asserted-by":"publisher","first-page":"3636","DOI":"10.4161\/cc.8.22.9890","article-title":"Insights into the function of the human P-TEFb component CDK9\u00a0in the regulation of chromatin modifications and co-transcriptional mRNA processing","volume":"8","author":"Pirngruber","year":"2009","journal-title":"Cell Cycle"},{"key":"2021112216050134900_B38","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.cell.2009.07.031","article-title":"Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation","volume":"138","author":"Zippo","year":"2009","journal-title":"Cell"},{"key":"2021112216050134900_B39","doi-asserted-by":"publisher","first-page":"460","DOI":"10.4161\/epi.5.6.12314","article-title":"Histone H2B ubiquitination and beyond: regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation","volume":"5","author":"Chandrasekharan","year":"2010","journal-title":"Epigenetics"},{"key":"2021112216050134900_B40","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1083\/jcb.200906005","article-title":"Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1","volume":"186","author":"Nakanishi","year":"2009","journal-title":"J. Cell. Biol."},{"key":"2021112216050134900_B41","doi-asserted-by":"publisher","first-page":"7220","DOI":"10.1128\/MCB.00274-07","article-title":"Functional analysis of the transcription repressor PLU-1\/JARID1B","volume":"27","author":"Scibetta","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"2021112216050134900_B42","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.molcel.2007.03.001","article-title":"PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation","volume":"25","author":"Yamane","year":"2007","journal-title":"Mol. Cell"},{"key":"2021112216050134900_B43","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1038\/sj.jid.5700324","article-title":"Re-expression of the retinoblastoma-binding protein 2-homolog 1 reveals tumor-suppressive functions in highly metastatic melanoma cells","volume":"126","author":"Roesch","year":"2006","journal-title":"J. Invest. Dermatol."},{"key":"2021112216050134900_B44","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/modpathol.3800413","article-title":"Retinoblastoma-binding protein 2-homolog 1: a retinoblastoma-binding protein downregulated in malignant melanomas","volume":"18","author":"Roesch","year":"2005","journal-title":"Mod. Pathol."},{"key":"2021112216050134900_B45","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1002\/ijc.23211","article-title":"RBP2-H1\/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells","volume":"122","author":"Roesch","year":"2008","journal-title":"Int. J. Cancer."},{"key":"2021112216050134900_B46","doi-asserted-by":"publisher","first-page":"6899","DOI":"10.1158\/0008-5472.CAN-11-1523","article-title":"Binding of the JmjC demethylase JARID1B to LSD1\/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14","volume":"71","author":"Li","year":"2011","journal-title":"Cancer Res."},{"key":"2021112216050134900_B47","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.ccr.2011.05.006","article-title":"Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth","volume":"19","author":"Mulholland","year":"2011","journal-title":"Cancer Cell"},{"key":"2021112216050134900_B48","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/ncb2139","article-title":"CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells","volume":"13","author":"Wei","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2021112216050134900_B49","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1038\/emboj.2012.112","article-title":"A transcriptional repressor co-regulatory network governing androgen response in prostate cancers","volume":"31","author":"Chng","year":"2012","journal-title":"EMBO J."},{"key":"2021112216050134900_B50","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/2043-9113-2-22","article-title":"mCOPA: analysis of heterogeneous features in cancer expression data","volume":"2","author":"Wang","year":"2012","journal-title":"J. Clin. Bioinforma."},{"key":"2021112216050134900_B51","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1002\/pros.21510","article-title":"Hexim-1 modulates androgen receptor and the TGF-\u03b2 signaling during the progression of prostate cancer","volume":"72","author":"Mascareno","year":"2012","journal-title":"Prostate"},{"key":"2021112216050134900_B52","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1210\/me.2010-0238","article-title":"CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation","volume":"24","author":"Gordon","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"2021112216050134900_B53","doi-asserted-by":"publisher","first-page":"29304","DOI":"10.1074\/jbc.M204131200","article-title":"Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites","volume":"277","author":"Gioeli","year":"2002","journal-title":"J. Biol. Chem."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/462\/2\/315\/679741\/bj4620315.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/462\/2\/315\/679741\/bj4620315.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T22:52:15Z","timestamp":1637621535000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/462\/2\/315\/47631\/HEXIM1-plays-a-critical-role-in-the-inhibition-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,7]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,9,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20140174","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,7]]}}}