3beta-HSD1-mediated steroid back-conversion maintains androgen signaling in prostate cancer

作者：Masoud Bitaraf, Mohammad Alyamani, Nikou Fotouhi, Jinyuan Shi, Ziqi Zhu, Yoon‐Mi Chung, Jennifer A. Freedman, Daniel J. George, Nima Sharifi · 发表于：Molecular Cancer Research · 年份：2026 · DOI：10.1158/1541-7786.mcr-26-0243 · 研究领域：Prostate Cancer Treatment and Research、Estrogen and related hormone effects、Hormonal Regulation and Hypertension

Dihydrotestosterone (DHT), the principal driver of prostate cancer, is inactivated via reduction of its 3-keto group to a 3β-hydroxyl (3β-OH). 3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1), encoded by HSD3B1, catalyzes 3β-OH oxidation and is stabilized by an adrenal-permissive germline variant, thereby enhancing androgen biosynthesis. Here, we tested whether 3β-HSD1 maintains androgen receptor (AR) signaling by back-converting the inactive metabolite 3β-androstanediol (3β-diol) to DHT, and whether it similarly oxidizes the abiraterone metabolite 3β-OH-5α-abiraterone (3β-OH-5α-Abi) to 3-keto-5α-Abi, a weak AR agonist. Using HSD3B1-overexpression and knockout in vitro models, we quantified steroid interconversion by mass spectrometry and AR-responsive gene expression by qPCR and RNA sequencing following 3β-diol exposure. HSD3B1 overexpression efficiently enabled the conversion of 3β-diol to DHT and 3β-OH-5α-Abi to 3-keto-5α-Abi. In C4-2 prostate cancer cells, 3β-diol-derived DHT regeneration and subsequent AR gene induction were blocked by the 3β-HSD1 inhibitor trilostane or abolished by HSD3B1 knockout. Clinically, in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone, apalutamide, and prednisone in the PANTHER trial, men harboring the adrenal-permissive HSD3B1 genotype showed significantly greater serum depletion of 3β-OH-5α-Abi. These findings demonstrate that 3β-HSD1-mediated steroid back-conversion can maintain i...