A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.
A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.
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DOI：
10.1016/j.cell.2013.07.029
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发表时间：
2013-08-29
期刊：
影响因子：
64.5
通讯作者：
Sharifi N
中科院分区：
文献类型：
--
作者：
Chang KH;Li R;Kuri B;Lotan Y;Roehrborn CG;Liu J;Vessella R;Nelson PS;Kapur P;Guo X;Mirzaei H;Auchus RJ;Sharifi N
前列腺癌细胞的生长依赖于雄激素受体（AR）的雄激素刺激。双氢睾酮（DHT）是最有效的雄激素，通常由睾丸分泌的睾酮在前列腺中合成。在化学或手术去势后，前列腺癌通常会因睾丸激素缺乏而缩小。然而，肿瘤经常复发，形成去势抵抗性前列腺癌（CRPC）。在这里，我们发现CRPC有时表达稳定性获得突变，导致3β-羟基类固醇脱氢酶1型（3β HSD 1）的功能获得，3 β HSD 1催化肾上腺源性类固醇脱氢表雄酮转化为DHT的初始限速步骤。突变（N367 T）不影响催化功能，但它使酶对泛素化和降解具有抗性，导致深度积累。而脱氢表雄酮转化为DHT通常是非常有限的，367 T的表达加速了这种转化，并提供了激活AR所必需的DHT。我们认为3β HSD 1是治疗CRPC的有效靶点。
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 leading to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in the 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.
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