Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation.
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.
Metzger
Eric
E
Universitäts-Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
Yin
Na
N
Wissmann
Melanie
M
Kunowska
Natalia
N
Fischer
Kristin
K
Friedrichs
Nicolaus
N
Patnaik
Debasis
D
Higgins
Jonathan M G
JM
Potier
Noelle
N
Scheidtmann
Karl-Heinz
KH
Buettner
Reinhard
R
Schüle
Roland
R
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013912:Threonine / Q000378:metabolism*; D046888:Tissue Array Analysis; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D002843:Chromatin; D006657:Histones; D011944:Receptors, Androgen; D013912:Threonine; C061570:protein kinase N; D011493:Protein Kinase C