Abstract
Lysine-Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but has a coactivator function on some genes through mechanisms that are unclear. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR-regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at thesesites. These findings show that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and that it has a distinct AR-linked coactivator function mediated by demethylation of other substrates.
Highlights
Androgen receptor (AR) is highly expressed in prostate cancer (PCa) cells and plays a pivotal role in PCa through transactivation of multiple genes (Green et al, 2012; Yuan et al, 2013)
Using Chromatin immunoprecipitation (ChIP)-seq for LSD1 in androgen treated PCa cells (LNCaP), in combination with previous ChIP-seq data for AR and gene expression arrays (Cai et al, 2011; Lupien et al, 2008; Wang et al, 2007b; Wang et al, 2009b; Yu et al, 2010), we found that ~20% of LSD1 and AR sites were overlapping (Figure 1A)
LSD1+ as compared to LSD1− AR binding sites were further enriched amongst DHTstimulated genes (~5–7 fold versus ~2-fold) (Figure 1D), and Binding and Expression Target Analysis (BETA) (Wang et al, 2013) confirmed that LSD1+ AR sites were significantly enriched for these genes (Figure S1B)
Summary
Androgen receptor (AR) is highly expressed in prostate cancer (PCa) cells and plays a pivotal role in PCa through transactivation of multiple genes (Green et al, 2012; Yuan et al, 2013). Patients with metastatic PCa are treated with androgen deprivation therapy (ADT) to block AR activity, but the tumors invariably relapse (castration-resistant prostate cancer, CRPC). AR expression is increased in CRPC and most AR stimulated genes are highly expressed, indicating that AR transcriptional activity has been substantially restored (Yuan et al, 2013). Patients treated with these agents still generally relapse within 1–2 years, and high levels of AR and of AR regulated genes in many of these relapsed tumors indicate that AR activity has again been restored. There is still a pressing need to better understand AR transcriptional mechanisms in order to develop further approaches for blocking or modulating its activity
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