Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression

Abstract

Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression. Recently, lysine-specific demethylase 1 (LSD1), the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9) only. Here, we identify the Jumonji C (JMJC) domain-containing protein JMJD2C as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor in vitro and in vivo. Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities.

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

“…Wissmann and colleagues [41] have demonstrated that JMJD2C, which demethylases H3K9me3, and LSD1, which specifically demethylases H3K9 me2/me1, interact and cooperatively stimulate AR-dependent gene transcription. Recently it has been also reported, in ERa regulated transcription, a coordinated interaction among ERa and the H3K9me3 demethylase JMJD2B, and the H3K4 methyltransferase MLL2 complex has been recently reported [42].…”

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

“…In line with this, epigenetic enzymes interpreting and modifying histones are often aberrantly expressed in PrCa (Cooper and Foster, 2009), such as class I HDACs, which are overexpressed in aggressive and hormone-refractory PrCa, thus contributing to androgen-independent, lethal PrCa's (Halkidou et al, 2004;Weichert et al, 2008). Eight KDMs are highly expressed in PrCa's (Metzger et al, 2005;Kahl et al, 2006;Wissmann et al, 2007). Various HDACs and KDMs were shown to regulate androgen receptor (AR)-mediated transcription, thus affecting gene expression patterns essential for PrCa proliferation, development and progression (Yamane et al, 2006;Wissmann et al, 2007;Wolf et al, 2007;Xiang et al, 2007;Welsbie et al, 2009).…”

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

“…Both amine oxidases and JmjC-domain proteins demethylate by oxidation or hydroxylation, processes directly affected under hypoxia [21]. One potential mechanism driving increased H3K4me3 may be hypoxia-induced inactivation of H3K4me3-specfic histone demethylases, which utilize molecular oxygen during enzymatic removal of methyl groups [22][23][24]. The observed modifications of histones provide a hypoxia-regulated platform for binding and interactions of additional chromatin modifiers, remodelers or regulators of transcription, further amplifying gene-specific response to hypoxic stress.…”