title: The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.
abstract: Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
authors.affiliation: Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. jfqi@sbmri.org
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qi
authors.forename: Manisha
authors.initials: M
authors.lastname: Tripathi
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.forename: Natasha
authors.initials: N
authors.lastname: Sahgal
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazil
authors.forename: Susan
authors.initials: S
authors.lastname: Ettinger
authors.forename: William J
authors.initials: WJ
authors.lastname: Placzek
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Claps
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Neil
authors.initials: N
authors.lastname: Bhowmick
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: C410798:AR protein, human; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins