Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4.
Demethylation at distinct lysine residues in histone H3 by lysine-specific demethylase 1 (LSD1) causes either gene repression or activation. As a component of co-repressor complexes, LSD1 contributes to target gene repression by removing mono- and dimethyl marks from lysine 4 of histone H3 (H3K4). In contrast, during androgen receptor (AR)-activated ... gene expression, LSD1 removes mono- and dimethyl marks from lysine 9 of histone H3 (H3K9). Yet, the mechanisms that control this dual specificity of demethylation are unknown. Here we show that phosphorylation of histone H3 at threonine 6 (H3T6) by protein kinase C beta I (PKCbeta(I), also known as PRKCbeta) is the key event that prevents LSD1 from demethylating H3K4 during AR-dependent gene activation. In vitro, histone H3 peptides methylated at lysine 4 and phosphorylated at threonine 6 are no longer LSD1 substrates. In vivo, PKCbeta(I) co-localizes with AR and LSD1 on target gene promoters and phosphorylates H3T6 after androgen-induced gene expression. RNA interference (RNAi)-mediated knockdown of PKCbeta(I) abrogates H3T6 phosphorylation, enhances demethylation at H3K4, and inhibits AR-dependent transcription. Activation of PKCbeta(I) requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C (PKC)-related kinase 1 (PRK1). Notably, increased levels of PKCbeta(I) and phosphorylated H3T6 (H3T6ph) positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PKCbeta(I) blocks AR-induced tumour cell proliferation in vitro and cancer progression of tumour xenografts in vivo. Together, our data establish that androgen-dependent kinase signalling leads to the writing of the new chromatin mark H3T6ph, which in consequence prevents removal of active methyl marks from H3K4 during AR-stimulated gene expression.
Mesh Terms:
Androgens, Animals, Cell Division, Cell Line, Tumor, Chromatin, Gene Expression Regulation, Gene Knockdown Techniques, Histone Demethylases, Histones, Humans, Lysine, Male, Methylation, Mice, Mice, Nude, Mice, SCID, Phosphorylation, Phosphothreonine, Promoter Regions, Genetic, Prostatic Neoplasms, Protein Kinase C, Signal Transduction, Xenograft Model Antitumor Assays
Androgens, Animals, Cell Division, Cell Line, Tumor, Chromatin, Gene Expression Regulation, Gene Knockdown Techniques, Histone Demethylases, Histones, Humans, Lysine, Male, Methylation, Mice, Mice, Nude, Mice, SCID, Phosphorylation, Phosphothreonine, Promoter Regions, Genetic, Prostatic Neoplasms, Protein Kinase C, Signal Transduction, Xenograft Model Antitumor Assays
Nature
Date: Apr. 01, 2010
PubMed ID: 20228790
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