LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription

Abstract

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…Recent evidence demonstrates that LSD1 participates in androgen receptor (AR) and estrogen receptor-dependent gene expression. LSD1 is implicated in H3K9 demethylation associated with PSA gene activation in an AR-dependent manner [30], and with activation of most ERa gene targets in MCF7 cells [31]. In our study, we show by qRT-PCR and immunoblotting that LSD1 is expressed in Sertoli cells and is recruited in vivo at the ERE2/3 sites of the faah gene both in the presence and in the absence of the ligand.…”

“…LSD1 is an amine oxidase, and thus its activity can be inhibited by monoamine oxidase inhibitors like pargyline (Parg) [21,31]. We found that treatment with Parg, as well as knock-down of lsd1 gene in Sertoli cells transfected with Fig.…”

“…More recently, the lysine-specific demethylase 1 (LSD1) has been demonstrated to control nuclear hormone receptor-dependent gene expression, by activating ER target genes [21,30], as well as androgen-receptor target genes like PSA [31]. On this background, we investigated the role of LSD1 in estrogen-regulated expression of the faah gene in Sertoli cells.…”

“…Recent studies highlight the importance of these chromatin modifications in the transcriptional regulation mediated by nuclear hormone receptors, and suggest that histone modifiers could be nuclear receptor coregulators [38]. LSD1 was identified as the first histone lysine demethylase that acts on either lysine 4 residues (H3K4) or lysine 9 (H3K9) on histone 3 [30,31] in a contextdependent manner, and acts as a transcriptional inhibitor or activator, respectively. LSD1 contains a SWIRM domain, which functions as a putative protein-protein interaction motif, and an amine oxidase domain that harbors the demethylase activity.…”

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…SUMO-3 can enhance AR transcriptional activity independent of its sumoylation activity (Zheng et al, 2006). LSD1 is a histone demethylase that recently was shown to act on the AR and be overexpressed in prostate cancer (Metzger et al, 2005).…”