title: A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.
abstract: Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kai-Hsiung
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kuri
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Claus G
authors.initials: CG
authors.lastname: Roehrborn
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, WA 91809, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, WA 91809, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 91809, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: sharifn@ccf.org.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D054875:Ubiquitination
chemical_list: D000728:Androgens; D013196:Dihydrotestosterone; D015096:3-Hydroxysteroid Dehydrogenases