Abstract A46: LSD1 globally mediates epigenetic modifications on androgen receptor-dependent enhancers

Abstract

Abstract Androgen receptor (AR) belongs to nuclear receptor superfamily and plays pivotal roles in development of prostate and prostate cancer. The lignded AR binds to AR responsive elements (ARE) on the enhancers and mediates the transcription activity. AR binding on chromatin appears to depend on the binding of pioneer factor FOXA1, which recognizes the active sites marked with high level of mono- or di-methylation of Histon 3 lysine 4 (H3K4me1-2) and then make the site accessible for AR binding. However, the in depth mechanism how FOXA1 opens the enhancer and whether this results in further chromatin modification remains unclear. Through ChIP-seq studies coupled with gene expression array, we have found LSD1 (lysine specific demethylase 1) together with its binding partner CoRest were recruited by FOXA1 to the AR-dependent enhancer and its histone demethylation functions were then activated by liganded AR. This results in the loss of methylation marks and activation of gene transcription but not affecting AR binding or AR-mediated nucleosome dynamics. In contrast to this activator function, LSD1 can also formed corepressor complex to suppress the transcription of a subset of genes. This comprehensive study clearly suggested distinct roles of LSD1 as a coactivator versus a corepressor in different protein complexes therefore to mediate different cell functions. Citation Format: Changmeng Cai, Housheng Hansen He, Myles Brown, Steven P. Balk. LSD1 globally mediates epigenetic modifications on androgen receptor-dependent enhancers. [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 A46.