A Gain-of-Function Mutation in a Steroidogenic Enzyme Promotes CRPC

The outgrowth of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy is dependent on increased androgen synthesis within tumors and sustained androgen receptor (AR) signaling. Although treatment with inhibitors of androgen synthesis such as abiraterone limits CRPC growth, dihydrotestosterone (DHT) can be synthesized from residual amounts of the steroid precursor dehydroepiandrosterone (DHEA). However, the mechanisms that enhance DHT production from DHEA and promote abiraterone resistance in CRPC remain poorly understood. Chang and colleagues identified a nonsynonymous point mutation in hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (HSD3B1), which encodes an enzyme, 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), that is required for the initial rate-limiting step of DHT synthesis from DHEA, in a subset of CRPC cell lines. In addition, the N367T substitution was detected in human CRPC tumor samples as a somatic mutation or in association with LOH and increased expression of mutant 3βHSD1 in patients with germline heterozygous inheritance and was selected for in xenograft tumors treated with abiraterone, supporting a role in abiraterone resistance. HSD3B1 mutation did not alter the enzymatic activity of 3βHSD1 but rather prevented its polyubiquitination by the E3 ubiquitin ligase autocrine mobility factor receptor and degradation via the endoplasmic reticulum–associated protein degradation (ERAD) pathway, resulting in increased 3βHSD1 protein accumulation in mutant CRPC cells. Expression of mutant 3βHSD1 augmented the flux of DHEA to DHT, enhanced expression of AR-regulated genes in CRPC cells, and accelerated the development of CRPC tumors in vivo, whereas depletion of the mutant protein impaired DHT synthesis, diminished prostate cancer cell proliferation, and inhibited CRPC xenograft growth. These findings show that 3βHSD1 mutation facilitates enhanced DHT synthesis following androgen deprivation and suggest that inhibition of this steroidogenic enzyme may limit prostate cancer progression and overcome abiraterone resistance in CRPC.

Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 2013;154:1074–84.

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