Abstract A21: Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed type of cancer and the second leading cause of death from cancer in males in the United States. The initial growth of most localized PCa is slow and androgen-dependent. Thus, surgical treatment (prostatectomy) and hormone therapy (androgen deprivation) are effective initially. However, many patients relapse and progress to a fatal androgen-independent and bone-metastatic stage shortly when both primary and secondary hormone therapies fail. Unfortunately, the current options for the metastatic hormone-refractory PCa are still limited and mostly ineffective, resulting in high mortality of this disease. Although dysregulated androgen receptor (AR) signaling pathway has been proposed to contribute to the development of hormone-resistance, the involved mechanisms are still not fully defined. Our present findings revealed that the orphan nuclear receptor TLX (NR2E1) exhibited increased expression patterns in androgen-independent and antiandrogen-resistant PCa cells, and also the high-grade and hormone-refractory clinical PCa tissues. Stable overexpression of TLX in AR-positive LNCaP cells could promote both androgen-independent and antiandrogen-resistant cell growth in vitro, and enhance tumor growth capacity in castrated male SCID mice in vivo. Decreased expression of AR and AR target genes in LNCaP-TLX cells were identified, while results of AR-promoter driven luciferase reporter assay also revealed that TLX overexpression could suppress the AR transcription in non-prostatic HEK293 cells. Furthermore, we also identified the direct binding site of TLX on the AR promoter by chromatin immunoprecipitation analyses in TLX-transfected HEK293 cells. The molecular mechanism may involve the TLX-mediated recruitment of lysine-specific demethylase 1 (LSD1) as treatment with an inhibitor of LSD1 pargyline could reverse the transrepressive regulation of TLX on AR-promoter driven luciferase activity and restore AR gene expression levels in LNCaP cells. In summary, our results showed for the first time that overexpression of TLX might contribute to the hormone-resistant PCa cell growth and advanced progression of PCa. LSD1 might serve as a corepressor in TLX-mediated direct transrepression on AR gene expression. This work is partly supported by an RGC-General Research Fund CUHK461012. Citation Format: Lin Jia, Dinglan Wu, Shan Yu, Franky Leung Chan. Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A21.