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Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer

Zemin Hou,Shengsong Huang,Zejie Mei,Longlong Chen,Jiacheng Guo,Yuanyuan Gao,Qian Zhuang,Xuebin Zhang,Qilong Tan,Tao Yang,Ying Liu,Yongnan Chi,Lifengrong Qi,Ting Jiang,Xuefeng Shao,Yan Wu,Xiaojun Xu,Jun Qin,Ruobing Ren,Huiru Tang,Denglong Wu,Zhenfei Li

Summary Prostate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens. In this study, mass-spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients. High doses of progesterone activate canonical and non-canonical androgen receptor (AR) target genes. Physiological levels of progesterone facilitate cell proliferation via GATA2. Inhibitors of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) has been discovered and shown to suppress the generation of progesterone, eliminating its transient and accumulating oncogenic effects. An increase in progesterone is associated with poor clinical outcomes in patients and may be used as a predictive biomarker. Overall, we demonstrate that progesterone acts as an oncogenic hormone in prostate cancer, and strategies to eliminate its oncogenic effects may benefit prostate cancer patients.