Cancer Cell Article Androgen Receptor Gene Expression in Prostate Cancer Is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine-Specific Demethylase 1 Changmeng Cai, 1 Housheng Hansen He, 2,3 Sen Chen, 1 Ilsa Coleman, 4 Hongyun Wang, 1 Zi Fang, 1 Shaoyong Chen, 1 Peter S. Nelson, 4 X. Shirley Liu, 3 Myles Brown, 2 and Steven P. Balk 1, * 1 Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA 2 Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA 3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA 4 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington 91809, USA *Correspondence: sbalk@bidmc.harvard.edu DOI 10.1016/j.ccr.2011.09.001 SUMMARY Androgen receptor (AR) is reactivated in castration-resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contrib- uting to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels, the AR binds this site and represses AR gene expression through recruitment of lysine-specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis, and proliferation while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation. INTRODUCTION The standard treatment for metastatic prostate cancer (PCa) is surgical or medical castration to reduce circulating androgens (androgen deprivation therapy [ADT]) and suppress activity of the androgen receptor (AR), but patients invariably relapse with more aggressive castration-resistant prostate cancer (CRPC). Significantly, early studies showed that AR was highly expressed in CRPC (Ruizeveld de Winter et al., 1994), and further studies in clinical samples and xenograft models have confirmed that AR mRNA is highly expressed and consistently increased in CRPC compared to levels prior to ADT (Taplin et al., 1995; Gregory et al., 2001; Holzbeierlein et al., 2004; Chen et al., 2004; Stan- brough et al., 2006). Multiple androgen regulated-genes, including prostate-specific antigen (PSA) and the TMPRSS2:ERG fusion gene, are also highly expressed in CRPC, indicating that AR tran- scriptional activity has been reactivated despite castrate serum androgen levels (Stanbrough et al., 2006; Cai et al., 2009). Mecha- nisms that may contribute to restoring AR activity in CRPC include AR mutations or alternative splicing, increased intratumoral androgen synthesis, increased coactivator expression, and acti- vation of several kinases that may directly or indirectly sensitize AR to low levels of androgens (Yuan and Balk, 2009). Moreover, studies in xenograft models indicate that even modest increases in AR protein expression may alone render tumors resistant to castration and to available AR antagonists (Chen et al., 2004). Despite the critical role AR plays in PCa development and progression to CRPC, the mechanisms that regulate its Significance This study shows that AR can function through a suppressor element to repress its own expression and the expression of additional genes, including those that mediate androgen synthesis. This negative feedback loop suppresses AR signaling at high androgen levels but allows increased AR and androgen synthesis in CRPC. Moreover, decreased androgen levels in CRPC, although adequate to stimulate AR on enhancer elements, may relieve AR suppression of genes mediating DNA synthesis/proliferation and thereby contribute to tumor growth. Distinct mechanisms of AR action on enhancer versus suppressor elements may make it possible to selectively augment AR transcriptional repressor function and thereby prevent or delay emergence of CRPC. Cancer Cell 20, 457–471, October 18, 2011 ª2011 Elsevier Inc. 457