Regulation of the androgen receptor by SET9-mediated methylation.
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.
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
Luke
L
Gaughan
Jacqueline
J
Stockley
Nan
N
Wang
Stuart R C
SR
McCracken
Achim
A
Treumann
Kelly
K
Armstrong
Fadhel
F
Shaheen
Kate
K
Watt
Iain J
IJ
McEwan
Chenguang
C
Wang
Richard G
RG
Pestell
Craig N
CN
Robson
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
D006657:Histones; D011944:Receptors, Androgen; D011495:Histone-Lysine N-Methyltransferase; D017430:Prostate-Specific Antigen; D008239:Lysine