HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens.
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™ 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 in parental hormone-dependent LNCaP cells results in resistance to the inhibitory action of anti-androgens. Conversely, ectopic expression of HEXIM1 in 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.
*Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
I-Ju
IJ
Yeh
†Division of General Medical Science-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
Kyung
K
Song
*Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
Bryan M
BM
Wittmann
‡Center for RNA Biology, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
Xiaodong
X
Bai
†Division of General Medical Science-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
David
D
Danielpour
*Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
Monica M
MM
Montano
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors / Q000378:metabolism
D000726:Androgen Antagonists; D000813:Anilides; C476123:HEXIM1 protein, human; D006657:Histones; D009570:Nitriles; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D014105:Tosyl Compounds; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D015741:Metribolone; C053541:bicalutamide; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human