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Regulation of the androgen receptor by SET9-mediated methylation.

Gaughan L, Stockley J, Wang N, McCracken SR, Treumann A, Armstrong K, Shaheen F, Watt K, McEwan IJ, Wang C, Pestell RG, Robson CN - Nucleic Acids Res. (2010)

Bottom Line: Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor.Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9.Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes.

View Article: PubMed Central - PubMed

Affiliation: Solid Tumour Target Discovery Group, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK. luke.gaughan@ncl.ac.uk

ABSTRACT
The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and anti-apoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment.

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Related in: MedlinePlus

Postulated model of SET9-mediated regulation of the AR. Our working model is that SET9 enhances AR activity by methylating the receptor and histone H3-K4. Step 1: SET9 is present at androgen response elements (AREs) in the absence of active AR to mono-methylate H3-K4. Step 2: Activation of the AR via dihydrotestosterone (DHT) binding enables interaction of SET9 and the AR followed by methylation of the receptor on lysine 632 that facilitates inter-domain interaction of the N- and C-termini of the AR. Step 3: Methylated AR associates with target genes and enhances transcription.
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Figure 8: Postulated model of SET9-mediated regulation of the AR. Our working model is that SET9 enhances AR activity by methylating the receptor and histone H3-K4. Step 1: SET9 is present at androgen response elements (AREs) in the absence of active AR to mono-methylate H3-K4. Step 2: Activation of the AR via dihydrotestosterone (DHT) binding enables interaction of SET9 and the AR followed by methylation of the receptor on lysine 632 that facilitates inter-domain interaction of the N- and C-termini of the AR. Step 3: Methylated AR associates with target genes and enhances transcription.

Mentions: The above findings indicate multiple roles for SET9 during AR-mediated transcription, including promoter and receptor methylation that are important for AR folding and recruitment to target genes (as illustrated in Figure 8, see Discussion section). To confirm the importance of direct AR methylation in the transcriptional process, we over-expressed wild-type AR or AR632 in AR negative PC3 cells and assessed endogenous PSA expression by quantitative PCR. As expected, wild-type AR markedly up-regulated PSA levels [as described in ref. (47)], while expression of the AR methylation site mutant failed to enhance gene expression indicating that AR methylation is necessary for receptor function in the context of chromatinized genes (Supplementary Figure S8).


Regulation of the androgen receptor by SET9-mediated methylation.

Gaughan L, Stockley J, Wang N, McCracken SR, Treumann A, Armstrong K, Shaheen F, Watt K, McEwan IJ, Wang C, Pestell RG, Robson CN - Nucleic Acids Res. (2010)

Postulated model of SET9-mediated regulation of the AR. Our working model is that SET9 enhances AR activity by methylating the receptor and histone H3-K4. Step 1: SET9 is present at androgen response elements (AREs) in the absence of active AR to mono-methylate H3-K4. Step 2: Activation of the AR via dihydrotestosterone (DHT) binding enables interaction of SET9 and the AR followed by methylation of the receptor on lysine 632 that facilitates inter-domain interaction of the N- and C-termini of the AR. Step 3: Methylated AR associates with target genes and enhances transcription.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045589&req=5

Figure 8: Postulated model of SET9-mediated regulation of the AR. Our working model is that SET9 enhances AR activity by methylating the receptor and histone H3-K4. Step 1: SET9 is present at androgen response elements (AREs) in the absence of active AR to mono-methylate H3-K4. Step 2: Activation of the AR via dihydrotestosterone (DHT) binding enables interaction of SET9 and the AR followed by methylation of the receptor on lysine 632 that facilitates inter-domain interaction of the N- and C-termini of the AR. Step 3: Methylated AR associates with target genes and enhances transcription.
Mentions: The above findings indicate multiple roles for SET9 during AR-mediated transcription, including promoter and receptor methylation that are important for AR folding and recruitment to target genes (as illustrated in Figure 8, see Discussion section). To confirm the importance of direct AR methylation in the transcriptional process, we over-expressed wild-type AR or AR632 in AR negative PC3 cells and assessed endogenous PSA expression by quantitative PCR. As expected, wild-type AR markedly up-regulated PSA levels [as described in ref. (47)], while expression of the AR methylation site mutant failed to enhance gene expression indicating that AR methylation is necessary for receptor function in the context of chromatinized genes (Supplementary Figure S8).

Bottom Line: Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor.Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9.Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes.

View Article: PubMed Central - PubMed

Affiliation: Solid Tumour Target Discovery Group, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK. luke.gaughan@ncl.ac.uk

ABSTRACT
The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and anti-apoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment.

Show MeSH
Related in: MedlinePlus