Phosphorylation of histone H3T6 by PKCβI controls demethylation at histone H3K4
Histone demethylation mechanisms The N-terminal tails of histones are subject to a variety of post-translational modifications; addition or removal of these marks by specific enzymes facilitates gene activation or silencing. Here, a mechanism is defined that modulates the activity of the dual specif...
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| Published in: | Nature (London) Vol. 464; no. 7289; pp. 792 - 796 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01.04.2010
|
| Subjects: | |
| ISSN: | 0028-0836, 1476-4687 |
| Online Access: | Get full text |
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| Summary: | Histone demethylation mechanisms
The N-terminal tails of histones are subject to a variety of post-translational modifications; addition or removal of these marks by specific enzymes facilitates gene activation or silencing. Here, a mechanism is defined that modulates the activity of the dual specificity histone demethylase LSD1 during androgen-dependent transcription. Androgen-dependent signalling through protein kinase C beta I leads to phosphorylation of a histone residue that prevents demethylation of an adjacent residue by LSD1. This mechanism may potentially be important in prostate cancer.
The amino-terminal tails of histone proteins are subject to a variety of post-translational modifications; addition or removal of these 'marks' facilitates gene activation or silencing. Here, a mechanism is defined that modulates the activity of the dual-specificity histone demethylase LSD1 during androgen-dependent transcription. Androgen-dependent signalling through protein kinase C beta I leads to phosphorylation of a histone amino acid, which prevents demethylation of an adjacent amino acid by LSD1.
Demethylation at distinct lysine residues in histone H3 by lysine-specific demethylase 1 (LSD1) causes either gene repression or activation
1
,
2
. 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)
1
,
3
. In contrast, during androgen receptor (AR)-activated gene expression, LSD1 removes mono- and dimethyl marks from lysine 9 of histone H3 (H3K9)
2
. 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 (PKCβ
I
, also known as PRKCβ) 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
, PKCβ
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 PKCβ
I
abrogates H3T6 phosphorylation, enhances demethylation at H3K4, and inhibits AR-dependent transcription. Activation of PKCβ
I
requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C (PKC)-related kinase 1 (PRK1)
4
. Notably, increased levels of PKCβ
I
and phosphorylated H3T6 (H3T6ph) positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PKCβ
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. |
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| ISSN: | 0028-0836 1476-4687 |
| DOI: | 10.1038/nature08839 |