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Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

2007; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/ncb1668

1476-4679

Eric Metzger, Na Yin, Melanie Wissmann, Natalia Kunowska, Kristin Fischer, Nicolaus Friedrichs, Debasis Patnaik, Jonathan M.G. Higgins, Noëlle Potier, Karl‐Heinz Scheidtmann, Reinhard Buettner, Roland Schüle,

Prostate Cancer Treatment and Research

Posttranslational modifications of histones such as methylation, acetylation and phosphorylation regulate chromatin structure and gene expression. Here we show that protein-kinase-C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor target genes. PRK1 is pivotal to androgen receptor function because PRK1 knockdown or inhibition impedes androgen receptor-dependent transcription. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation and inhibits androgen-induced demethylation of histone H3. Moreover, serine-5-phosphorylated RNA polymerase II is no longer observed at androgen receptor target promoters. Phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC)-domain-containing protein JMJD2C. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for gene activation, identifying PRK1 as a gatekeeper of androgen receptor-dependent transcription. Importantly, levels of PRK1 and phosphorylated H3T11 correlate with Gleason scores of prostate carcinomas. Finally, inhibition of PRK1 blocks proliferation of androgen receptor-induced tumour cell proliferation, making PRK1 a promising therapeutic target.