Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1.
Androgen receptor (AR) is reactivated in castration-resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contributing to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels, the AR binds this site and represses AR gene expression through recruitment of lysine-specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis, and proliferation while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation.
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Changmeng
C
Cai
Housheng Hansen
HH
He
Sen
S
Chen
Ilsa
I
Coleman
Hongyun
H
Wang
Zi
Z
Fang
Shaoyong
S
Chen
Peter S
PS
Nelson
X Shirley
XS
Liu
Myles
M
Brown
Steven P
SP
Balk
D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*
D000728:Androgens; D006657:Histones; D012333:RNA, Messenger; D011944:Receptors, Androgen; D056466:Histone Demethylases; C495195:KDM1A protein, human