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: Kai-Hsiung Chang, Rui Li, Barbara Kuri, Yair Lotan, Claus G Roehrborn, Jiayan Liu, Robert Vessella, Peter S Nelson, Payal Kapur, Xiaofeng Guo, Hamid Mirzaei, Richard J Auchus, Nima Sharifi
• Journal: Cell (Cell) Vol. 154 Issue 5 Pg. 1074-1084 (Aug 29 2013) ISSN: 1097-4172 [Electronic] United States
• PMID: 23993097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Androgens
• Dihydrotestosterone
• 3-Hydroxysteroid Dehydrogenases

Topics

• 3-Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Androgens (metabolism)
• Animals
• Dihydrotestosterone (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Prostatic Neoplasms (enzymology, genetics, metabolism)
• Proteolysis
• Ubiquitination