Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer.
Transcriptional activity of the androgen receptor (AR) is crucial for growth and survival of prostate cancer even upon development of resistance to androgen ablation and antiandrogen therapies. Therefore, novel therapies that can suppress AR transcriptional activity when conventional hormone therapies fail are needed. Here, we show that histone deacetylase (HDAC) inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in clinic, could be such a therapy. HDAC inhibitors block the AR-mediated transcriptional activation of many genes, including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. Genetic knockdown of either HDAC1 or HDAC3 can also suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment. Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in castration-resistant prostate cancer models and, therefore, merit clinical investigation in this setting. The HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.
Welsbie
Derek S
DS
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Xu
Jin
J
Chen
Yu
Y
Borsu
Laetitia
L
Scher
Howard I
HI
Rosen
Neal
N
Sawyers
Charles L
CL
D059002:Androgen Receptor Antagonists; D000818:Animals; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D059002:Androgen Receptor Antagonists; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D011944:Receptors, Androgen; D012319:RNA Polymerase II; D006655:Histone Deacetylases