title: Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth.
abstract: 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.
authors: Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors: Maofu
authors: M
authors: Fu
authors: Mahadev
authors: M
authors: Rao
authors: Chenguang
authors: C
authors: Wang
authors: Toshiyuki
authors: T
authors: Sakamaki
authors: Jian
authors: J
authors: Wang
authors: Dolores
authors: D
authors: Di Vizio
authors: Xueping
authors: X
authors: Zhang
authors: Chris
authors: C
authors: Albanese
authors: Steven
authors: S
authors: Balk
authors: Chawnshang
authors: C
authors: Chang
authors: Saijun
authors: S
authors: Fan
authors: Eliot
authors: E
authors: Rosen
authors: Jorma J
authors: JJ
authors: Palvimo
authors: Olli A
authors: OA
authors: Jänne
authors: Selen
authors: S
authors: Muratoglu
authors: Maria Laura
authors: ML
authors: Avantaggiati
authors: Richard G
authors: RG
authors: Pestell
mesh_terms: 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
chemical_list: 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