Phosphorylation of histone H3T6 by PKCb sub(I) controls demethylation at histone H3K4

• Published in: Nature (London) Vol. 464; no. 7289; pp. 792 - 796
• Main Authors: Metzger, Eric, Imhof, Axel, Patel, Dharmeshkumar, Kahl, Philip, Hoffmeyer, Katrin, Friedrichs, Nicolaus, Mueller, Judith M, Greschik, Holger, Kirfel, Jutta, Ji, Sujuan, Kunowska, Natalia, Beisenherz-Huss, Christian, Guenther, Thomas, Buettner, Reinhard, Schuele, Roland
• Format: Journal Article
• Language: English
• Published: 01.04.2010
• ISSN: 0028-0836
• DOI: 10.1038/nature08839

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 threonine6 (H3T6) by protein kinase C beta I (PKCb sub(I), also known as PRKCb) 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, PKCb sub(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 PKCb sub(I) abrogates H3T6 phosphorylation, enhances demethylation at H3K4, and inhibits AR-dependent transcription. Activation of PKCb sub(I) requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C (PKC)-related kinase 1 (PRK1). Notably, increased levels of PKCb sub(I) and phosphorylated H3T6 (H3T6ph) positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PKCb sub(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.