Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth.
Modification by acetylation occurs at epsilon-amino lysine residues of histones and transcription factors. Unlike phosphorylation, a direct link between transcription factor acetylation and cellular growth or apoptosis has not been established. We show that the nuclear androgen receptor (AR), a DNA-binding transcriptional regulator, is acetylated in vivo. The acetylation of the AR is induced by ligand dihydrotestosterone and by histone deacetylase (HDAC) inhibitors in living cells. Direct AR acetylation augmented p300 binding in vitro. Constructs mimicking neutral polar substitution acetylation (AR(K630Q), AR(K630T)) enhanced p300 binding and reduced N-CoR/HDAC/Smad3 corepressor binding, whereas charged residue substitution (AR(K630R)) reduced p300 binding and enhanced corepressor binding. The AR acetylation mimics promoted cell survival and growth of prostate cancer cells in soft agar and in nude mice and augmented transcription of a subset of growth control target gene promoters. Thus, transcription factor acetylation regulates coactivator/corepressor complex binding, altering expression of specific growth control genes to promote aberrant cellular growth in vivo.
Fu
Maofu
M
Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
Rao
Mahadev
M
Wang
Chenguang
C
Sakamaki
Toshiyuki
T
Wang
Jian
J
Di Vizio
Dolores
D
Zhang
Xueping
X
Albanese
Chris
C
Balk
Steven
S
Chang
Chawnshang
C
Fan
Saijun
S
Rosen
Eliot
E
Palvimo
Jorma J
JJ
Jänne
Olli A
OA
Muratoglu
Selen
S
Avantaggiati
Maria Laura
ML
Pestell
Richard G
RG
D000107:Acetylation; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D050881:E1A-Associated p300 Protein; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D015534:Trans-Activators; D013196:Dihydrotestosterone; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D006655:Histone Deacetylases