title: The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells.
abstract: Re-activation of androgen receptor (AR) activity is the main driver for development of castration-resistant prostate cancer. We previously reported that the ubiquitin ligase Siah2 enhanced AR transcriptional activity and prostate cancer cell growth. Among the genes we found to be regulated by Siah2 was AKR1C3, which encodes a key androgen biosynthetic enzyme implicated in castration-resistant prostate cancer development. Here, we found that Siah2 inhibition in CWR22Rv1 prostate cancer cells decreased AKR1C3 expression as well as intracellular androgen levels, concomitant with inhibition of cell growth in vitro and in orthotopic prostate tumors. Re-expression of either wild-type or catalytically inactive forms of AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, suggesting a nonenzymatic role for AKR1C3 in these outcomes. Unexpectedly, AKR1C3 re-expression in Siah2 knockdown cells elevated Siah2 protein levels, whereas AKR1C3 knockdown had the opposite effect. We further found that AKR1C3 can bind Siah2 and inhibit its self-ubiquitination and degradation, thereby increasing Siah2 protein levels. We observed parallel expression of Siah2 and AKR1C3 in human prostate cancer tissues. Collectively, our findings identify a new role for AKR1C3 in regulating Siah2 stability and thus enhancing Siah2-dependent regulation of AR activity in prostate cancer cells.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Lingling
authors.initials: L
authors.lastname: Fan
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Guihong
authors.initials: G
authors.lastname: Peng
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201.
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Guns
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: JQI@som.umaryland.edu.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qi
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000201:enzymology* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D000098563:Seven in Absentia Proteins
chemical_list: C410798:AR protein, human; D000728:Androgens; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D017430:Prostate-Specific Antigen; D046988:Proteasome Endopeptidase Complex
keywords: androgen; androgen receptor; prostate cancer; transcription regulation; ubiquitin ligase