Publication Date:
2010-03-17
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metzger, Eric -- Imhof, Axel -- Patel, Dharmeshkumar -- Kahl, Philip -- Hoffmeyer, Katrin -- Friedrichs, Nicolaus -- Muller, Judith M -- Greschik, Holger -- Kirfel, Jutta -- Ji, Sujuan -- Kunowska, Natalia -- Beisenherz-Huss, Christian -- Gunther, Thomas -- Buettner, Reinhard -- Schule, Roland -- England -- Nature. 2010 Apr 1;464(7289):792-6. doi: 10.1038/nature08839. Epub 2010 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Urologische Klinik/Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universitat Freiburg, Breisacherstrasse 66, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20228790" target="_blank"〉PubMed〈/a〉
Keywords:
Androgens/metabolism/pharmacology
;
Animals
;
Cell Division/drug effects
;
Cell Line, Tumor
;
Chromatin/metabolism
;
Gene Expression Regulation/drug effects
;
Gene Knockdown Techniques
;
Histone Demethylases/antagonists & inhibitors/*metabolism
;
Histones/*chemistry/*metabolism
;
Humans
;
Lysine/chemistry/metabolism
;
Male
;
Methylation/drug effects
;
Mice
;
Mice, Nude
;
Mice, SCID
;
Phosphorylation/drug effects
;
Phosphothreonine/metabolism
;
Promoter Regions, Genetic/genetics
;
Prostatic Neoplasms/enzymology/metabolism/pathology
;
Protein Kinase C/antagonists & inhibitors/deficiency/genetics/*metabolism
;
Protein Kinase C beta
;
Signal Transduction/drug effects
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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