A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer

Kai Hsiung Chang, Rui Li, Barbara Kuri, Yair Lotan, Claus Roehrborn, Jiayan Liu, Robert Vessella, Peter S. Nelson, Payal Kapur, Xiaofeng Guo, Hamid Mirzaei, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

155 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1074-1084
Number of pages11
JournalCell
Volume154
Issue number5
DOIs
StatePublished - Aug 29 2013

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Dihydrotestosterone
Castration
Prostatic Neoplasms
3-Hydroxysteroid Dehydrogenases
Mutation
Dehydroepiandrosterone
Androgen Receptors
Androgens
Testosterone
Ubiquitination
Tumors
Steroids
Cells
Testis
Prostate
Degradation
Enzymes
Growth
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. / Chang, Kai Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus; Liu, Jiayan; Vessella, Robert; Nelson, Peter S.; Kapur, Payal; Guo, Xiaofeng; Mirzaei, Hamid; Auchus, Richard J.; Sharifi, Nima.

In: Cell, Vol. 154, No. 5, 29.08.2013, p. 1074-1084.

Research output: Contribution to journalArticle

Chang, KH, Li, R, Kuri, B, Lotan, Y, Roehrborn, C, Liu, J, Vessella, R, Nelson, PS, Kapur, P, Guo, X, Mirzaei, H, Auchus, RJ & Sharifi, N 2013, 'A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer', Cell, vol. 154, no. 5, pp. 1074-1084. https://doi.org/10.1016/j.cell.2013.07.029
Chang, Kai Hsiung ; Li, Rui ; Kuri, Barbara ; Lotan, Yair ; Roehrborn, Claus ; Liu, Jiayan ; Vessella, Robert ; Nelson, Peter S. ; Kapur, Payal ; Guo, Xiaofeng ; Mirzaei, Hamid ; Auchus, Richard J. ; Sharifi, Nima. / A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. In: Cell. 2013 ; Vol. 154, No. 5. pp. 1074-1084.
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