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Phosphorylation of histone H3T6 by PKCβI controls demethylation at histone H3K4.

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Title: Phosphorylation of histone H3T6 by PKCβI controls demethylation at histone H3K4.
Authors: Metzger, Eric, Imhof, Axel, Patel, Dharmeshkumar, Kahl, Philip, Hoffmeyer, Katrin, Friedrichs, Nicolaus, Müller, Judith M., Greschik, Holger, Kirfel, Jutta, Sujuan Ji, Kunowska, Natalia, Beisenherz-Huss, Christian, G&x00FC;nther, Thomas, Buettner, Reinhard, Schüle, Roland
Source: Nature. 4/1/2010, Vol. 464 Issue 7289, p792-796. 5p. 4 Graphs.
Subjects: Phosphorylation, Gene expression, Cell proliferation, Cancer cells, Protein kinase C, Androgens, Peptides, RNA, Ethanes, Transcription factors
Abstract: 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 (PKCβI, 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, PKCβI co-localizes with AR and LSD1 on target gene promoters and phosphorylates H3T6 after androgen-induced gene expression. RNA interference (RNAi)-mediated knockdown of PKCβI abrogates H3T6 phosphorylation, enhances demethylation at H3K4, and inhibits AR-dependent transcription. Activation of PKCβI requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C (PKC)-related kinase 1 (PRK1). Notably, increased levels of PKCβI and phosphorylated H3T6 (H3T6ph) positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PKCβI 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. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Phosphorylation of histone H3T6 by PKCβ<subscript>I</subscript> controls demethylation at histone H3K4.
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  Data: <searchLink fieldCode="AR" term="%22Metzger%2C+Eric%22">Metzger, Eric</searchLink><br /><searchLink fieldCode="AR" term="%22Imhof%2C+Axel%22">Imhof, Axel</searchLink><br /><searchLink fieldCode="AR" term="%22Patel%2C+Dharmeshkumar%22">Patel, Dharmeshkumar</searchLink><br /><searchLink fieldCode="AR" term="%22Kahl%2C+Philip%22">Kahl, Philip</searchLink><br /><searchLink fieldCode="AR" term="%22Hoffmeyer%2C+Katrin%22">Hoffmeyer, Katrin</searchLink><br /><searchLink fieldCode="AR" term="%22Friedrichs%2C+Nicolaus%22">Friedrichs, Nicolaus</searchLink><br /><searchLink fieldCode="AR" term="%22Müller%2C+Judith+M%2E%22">Müller, Judith M.</searchLink><br /><searchLink fieldCode="AR" term="%22Greschik%2C+Holger%22">Greschik, Holger</searchLink><br /><searchLink fieldCode="AR" term="%22Kirfel%2C+Jutta%22">Kirfel, Jutta</searchLink><br /><searchLink fieldCode="AR" term="%22Sujuan+Ji%22">Sujuan Ji</searchLink><br /><searchLink fieldCode="AR" term="%22Kunowska%2C+Natalia%22">Kunowska, Natalia</searchLink><br /><searchLink fieldCode="AR" term="%22Beisenherz-Huss%2C+Christian%22">Beisenherz-Huss, Christian</searchLink><br /><searchLink fieldCode="AR" term="%22G%26x00FC%3Bnther%2C+Thomas%22">G&x00FC;nther, Thomas</searchLink><br /><searchLink fieldCode="AR" term="%22Buettner%2C+Reinhard%22">Buettner, Reinhard</searchLink><br /><searchLink fieldCode="AR" term="%22Schüle%2C+Roland%22">Schüle, Roland</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 4/1/2010, Vol. 464 Issue 7289, p792-796. 5p. 4 Graphs.
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  Data: 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 (PKCβI, 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, PKCβI co-localizes with AR and LSD1 on target gene promoters and phosphorylates H3T6 after androgen-induced gene expression. RNA interference (RNAi)-mediated knockdown of PKCβI abrogates H3T6 phosphorylation, enhances demethylation at H3K4, and inhibits AR-dependent transcription. Activation of PKCβI requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C (PKC)-related kinase 1 (PRK1). Notably, increased levels of PKCβI and phosphorylated H3T6 (H3T6ph) positively correlate with high Gleason scores of prostate carcinomas, and inhibition of PKCβI 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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