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Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4.

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.

Pubmed ID: 20228790


  • Metzger E
  • Imhof A
  • Patel D
  • Kahl P
  • Hoffmeyer K
  • Friedrichs N
  • Müller JM
  • Greschik H
  • Kirfel J
  • Ji S
  • Kunowska N
  • Beisenherz-Huss C
  • Günther T
  • Buettner R
  • Schüle R



Publication Data

April 1, 2010

Associated Grants


Mesh Terms

  • Androgens
  • Animals
  • Cell Division
  • Cell Line, Tumor
  • Chromatin
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Histone Demethylases
  • Histones
  • Humans
  • Lysine
  • Male
  • Methylation
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Phosphorylation
  • Phosphothreonine
  • Promoter Regions, Genetic
  • Prostatic Neoplasms
  • Protein Kinase C
  • Protein Kinase C beta
  • Signal Transduction
  • Xenograft Model Antitumor Assays