A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer
Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence des mécanismes par lesquels une mutation d'un gène codant pour une déshydrogénase impliquée dans la régulation de la synthèse de la dihydrotestostérone favorise une résistance à la castration
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 3²-hydroxysteroid dehydrogenase type 1 (3²HSD1), 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 3²HSD1 is a valid target for the treatment of CRPC. "3²HSD1 catalyzes a rate-limiting step for DHT synthesis in CRPC "Selection for N367T mutant 3²HSD1 occurs in human CRPC tumors "The N367T 3²HSD1 mutation confers resistance to ubiquitination and degradation "Mutant 3²HSD1 protein accumulates, increasing DHT synthesis and causing CRPC Dihydrotestosterone (DHT), a potent androgen secreted by the testis, promotes the development of prostate cancer. Castration limits tumor growth, but castration-resistant tumors often recur. A gain-of-stability mutation in the enzyme 3²HSD1, an upstream regulator of DHT biosynthesis, drives this resistance and may be a valid therapeutic target.