TY - JOUR
T1 - XA gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer
AU - Chang, Kai Hsiung
AU - Li, Rui
AU - Kuri, Barbara
AU - Lotan, Yair
AU - Roehrborn, Claus
AU - Liu, Jiayan
AU - Vessella, Robert
AU - Nelson, Peter S.
AU - Kapur, Payal
AU - Guo, Xiaofeng
AU - Mirzaei, Hamid
AU - Auchus, Richard J.
AU - Sharifi, Nima
N1 - Funding Information:
We thank Ralph Deberardinis, Mike Brown, Kevin Courtney, George DeMartino, and Eugene Frenkel for helpful comments, Russell DeBose-Boyd for the anti-AFMR antibody, J.T. Hsieh for the anti-SKP2 antibody, Cheng-Ming Chiang for the anti-His antibody and Actinomycin D, David Trudgian for assistance with protein mass spectrometry, and An Jia and Chul Ahn for assistance with statistical analysis. This publication has been funded in part by a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), by the Prostate Cancer Foundation (to N.S., R.V., and P.S.N.), by an American Cancer Society Research Scholar Award (12-038-01-CCE [to N.S.]), by a grant from the U.S. Army Medical Research and Materiel Command (PC080193) (to N.S.), and additional grants from the National Cancer Institute (1R01CA168899 and 1R01CA172382-01 [to N.S.]). The acquisition of metastatic tumors through the UW Rapid Autopsy Program was funded in part by grants (PO1-CA85859 [to R.V. and P.S.N.], PC093509 [to P.S.N.], P01-CA163227 [P.S.N.], and P50CA097186 [R.V. and P.S.N.]).
PY - 2013/8/29
Y1 - 2013/8/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883367616&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883367616&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.07.029
DO - 10.1016/j.cell.2013.07.029
M3 - Article
C2 - 23993097
AN - SCOPUS:84883367616
SN - 0092-8674
VL - 154
SP - X1074-1084
JO - Cell
JF - Cell
IS - 5
ER -