Regulation of the androgen receptor by SET9-mediated methylation

Gaughan, Luke; Stockley, Jacqueline; Wang, Nan; McCracken, Stuart; Treumann, Achim; Armstrong, Kelly; Shaheen, Fadhel S.; Watt, Kate; McEwan, Iain J.; Wang, Chenguang; Pestell, Richard G.; Robson, Craig

doi:10.1093/nar/gkq861

Cited by 106 publications

(94 citation statements)

References 58 publications

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“…1D). A much longer AR fragment (AAs 601-700), as used in our study, is likely to have a very different conformation at the KLKK motif than an 18-mer peptide, as used in the other study (18). In our study, the pan-methyllysine antibody did not recognize the AR-K630A immunoprecipitate from transfected HEK 293A cells (Fig.…”

Section: Discussionmentioning

confidence: 50%

Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase

Ahn

Song

et al. 2011

Molecular Endocrinology

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Lysine methyltransferases modulate activities of transcription factors and transcription coregulators by methylating specific lysine residue(s). We report that the androgen receptor (AR) is methylated at lysine-630 by Set9, which was originally identified as a histone H3K4 monomethyltransferase. Alanine substitution of lysine-630 prevented AR methylation in vitro and in vivo. Set9 methylated the nuclear and cytoplasmic AR utilizing the cofactor S-adenosyl-methionine. A pan-methyllysine antibody recognized endogenous AR, and Set9 coimmunoprecipitated with nuclear and cytoplasmic AR. Set9 overexpression potentiated AR-mediated transactivation of the probasin promoter, whereas Set9 depletion inhibited AR activity and target gene expression. Similar to AR, chromatin occupancy of Set9 at androgen response elements (AREs) was androgen dependent, and associated with methylated histone H3K4 chromatin activation marks and p300/CBP associated factor acetyltransferase recruitment. Set9 depletion increased the histone H3K9-dimethyl repressive mark at AREs and reduced histone activation marks and occupancy of p300/CBP associated factor. K630A mutation reduced amino- and carboxy-terminal (N-C) interaction in Set9-intact cells, whereas N-C interaction for wild-type AR was reduced upon Set9 depletion. The K630A mutant was resistant to loss of activity from Set9 silencing and to increase of activity from Set9 overexpression. The K630 dependence of Set9-regulated N-C interaction and AR activity suggests that Set9 directly acts on AR at the amino acid level. Chromatin recruitment of Set9 to AREs is suggestive of its additional role as a transcriptional coactivator. Because the cellular metabolic state determines the level of S-adenosylmethionine and consequently the activity of Set9, the enhanced activity of methylated AR may have special significance in certain metabolic contexts.

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Section: Discussionmentioning

confidence: 50%

Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase

Ahn

Song

et al. 2011

Molecular Endocrinology

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“…AR is methylated on two residues, K630 and K632, by SETD7 [24,25]. As is the case for methylation of ERa by SETD7, these methyl marks on AR enhance its transcriptional activity.…”

Section: Era and Other Nuclear Receptorsmentioning

confidence: 98%

“…For example, SETD7 methylates androgen receptor (AR) and enhances AR-mediated transactivation. This methylation facilitates the inter-domain communication and the recruitment of AR to chromatin, while the overall AR protein level is not affected [24,25]. Likewise, SETD7-mediated methylation of farnesoid X receptor (FXR) stimulates its transcriptional activation activity without altering protein stability [26].…”

Section: Setd7mentioning

confidence: 99%

Emerging roles of lysine methylation on non-histone proteins

Zhang

Huang

Shi

2015

Cell. Mol. Life Sci.

124

103

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Lysine methylation is a common posttranslational modification (PTM) of histones that is important for the epigenetic regulation of transcription and chromatin in eukaryotes. Increasing evidence demonstrates that in addition to histones, lysine methylation also occurs on various non-histone proteins, especially transcription- and chromatin-regulating proteins. In this review, we will briefly describe the histone lysine methyltransferases (KMTs) that have a broad spectrum of non-histone substrates. We will use p53 and nuclear receptors, especially estrogen receptor alpha, as examples to discuss the dynamic nature of non-histone protein lysine methylation, the writers, erasers, and readers of these modifications, and the crosstalk between lysine methylation and other PTMs in regulating the functions of the modified proteins. Understanding the roles of lysine methylation in normal cells and during development will shed light on the complex biology of diseases associated with the dysregulation of lysine methylation on both histones and non-histone proteins.

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“…Me and demethylation of histone proteins are emerging as a key process in the initiation and regulation of transcription. Furthermore, many lysine demethylases (KDMs) and methyltransferases (KMTs) have been detailed as nuclear receptor coregulator proteins with direct AR-Me being documented in 2011 by Gaughan et al (2011), which was quickly followed by a second report by Ko et al (2011). Both studies described Set9-mediated AR-Me as To date, these are the only two studies that describe direct Me of the AR, while demethylation of the AR has not yet been reported.…”

Section: Me Of the Armentioning

confidence: 99%

Regulation of the androgen receptor by post-translational modifications

Coffey

Robson

2012

Journal of Endocrinology

121

100

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The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.

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Regulation of the androgen receptor by SET9-mediated methylation

Cited by 106 publications

References 58 publications

Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase

Lysine Methylation and Functional Modulation of Androgen Receptor by Set9 Methyltransferase

Emerging roles of lysine methylation on non-histone proteins

Regulation of the androgen receptor by post-translational modifications

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