Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 16 S8.3

Nuclear receptors

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

Eric Metzger1, Na Yin1, Melanie Wissmann1, Natalia Kunowska1, Nicolaus Friedrichs2, Debasis Patnaik3, Jonathan M G Higgins3, Noelle Potier4, Karl-Heinz Scheidtmann5, Reinhard Buettner2 & Roland Schüle1


1Universitäts-Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany; 2Institut für Pathologie, Universitätsklinikum Bonn, Bonn, Germany; 3Division of Rheumatology, Immunology and Allergy, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 4Institut de Chimie LC3 - CNRS- UMR 7177, ISIS, Strasbourg, France; 5Institut für Genetik, Universität Bonn, Bonn, Germany.

Post-translational modifications of histones such as methylation, acetylation, and phoshorylation regulate chromatin structure and gene expression. However, phosphorylation of histone H3 at threonine 11 (H3T11ph) has not been linked to transcriptional regulation. Here we show that protein kinase C-related kinase 1 (PRK1) phosphorylates H3T11 upon ligand-dependent recruitment to androgen receptor (AR) target genes. PRK1 is pivotal to AR function since PRK1 knockdown by RNAi or PRK1 inhibition by treatment with Ro318220 impedes AR-dependent gene expression. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation, and in consequence, inhibits androgen-induced demethylation of histone H3 in vivo. Moreover, the presence of serine 5-phosphorylated RNA polymerase II is no longer observed at AR target promoters. In vitro, phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC) domain-containing protein JMJD2C3. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for transcriptional activation, identifying PRK1 as a gatekeeper of AR-regulated gene expression. Importantly, elevated PRK1- and H3T11ph levels positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PRK1 blocks AR-induced tumour cell proliferation. Thus, PRK1 is a promising therapeutic target in the treatment of prostate cancer.

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