Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

Abstract

SUMMARY Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. 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 these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates.

Regulation of vascular endothelial growth factor in prostate cancer

“…Although KDM1A acts predominantly as a transcriptional corepressor, it can act as a coactivator for AR (Metzger et al 2005) and ERa (Perillo et al 2008), depending on promoter context (Cai et al 2011). Consistent with this, there is evidence that KDM1A can contribute to hormone refractory PCa by sensitizing prostate cells to lower androgen levels (Cai et al 2011(Cai et al , 2014. ARs and ERs are known to cooperate in gene regulation in PCa and can define transcriptional signatures associated with aggressive disease (Setlur et al 2008).…”

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

“…LSD1 is present in different protein complexes, such as the HDAC/CoREST/REST complex (Lee et al, 2005;Shi et al, 2005) and the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex (Wang et al, 2009), and displays diverse functions. Even in the HDAC/CoREST/REST complex, LSD1 could either positively or negatively regulate androgen receptor (AR)-associated genes, dependent on its demethylation substrates (Cai et al, 2014). As a component of the NuRD complex, LSD1 can directly interact with one of the three metastasis tumor antigens (MTA) 1/2/3, which in turn target promoter regions of genes and control gene expression (Wang et al, 2009).…”

Tissue control of androgen action: The ups and downs of androgen receptor expression

“…Auto-repression of the AR mRNA has also been observed in a number of human cell-lines (Shan et al 1990;Quarmby et al 1990;Krongrad et al 1991;Wolf et al 1993) A second inhibitory ARE is situated in intron 2 over 100k bp downstream of the main promoter (Cai et al 2011) (Figure 2). The mechanism of action has been elucidated, with the chromatin remodelling enzyme LSD1 being recruited by ARE-bound activated AR resulting in histone H3K4me1,2 demethylation and subsequent downregulation (Cai et al 2014). A role for the pioneer transcription factor FOXA1, in this negative regulation, has also been identified (Jones et al 2015).…”