Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer
Xuebin Zhang, … , Denglong Wu, Zhenfei Li
Xuebin Zhang, … , Denglong Wu, Zhenfei Li
Published December 15, 2023
Citation Information: J Clin Invest. 2023;133(24):e171199. https://doi.org/10.1172/JCI171199.
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Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer

Abstract

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.

Authors

Xuebin Zhang, Zengming Wang, Shengsong Huang, Dongyin He, Weiwei Yan, Qian Zhuang, Zixian Wang, Chenyang Wang, Qilong Tan, Ziqun Liu, Tao Yang, Ying Liu, Ruobing Ren, Jing Li, William Butler, Huiru Tang, Gong-Hong Wei, Xin Li, Denglong Wu, Zhenfei Li

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Figure 9

Equilin suppresses UBE3D-related tumor aggressiveness.

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Equilin suppresses UBE3D-related tumor aggressiveness. (A) Schema of 3βH...
(A) Schema of 3βHSD1 inhibitor screening. (B) Screening results of 176 potential hits. LNCaP cells were treated with [3H]-DHEA and potential hits for DHEA metabolism. Inhibitory efficacy was compared with that of biochanin A (BCA). (C) Equilin inhibited DHEA utilization in VCaP cells more potently. [3H]-DHEA was used to treat VCaP cells with different doses of equilin and BCA. (D) Equilin inhibited the activity of purified 3βHSD1 more potently. GST-3βHSD1 (2 μg) was used for the in vitro enzyme activity assays. (E) Affinity of equilin and BCA to purified 3βHSD1 protein determined by surface plasmon resonance technology. Data were fitted with a 1:1 kinetic binding model as binding affinity (KD) indicated. (F and G) Equilin inhibited the expression of AR target gene. DHEA, 100 nM. Charcoal-stripped serum was used for starvation before DHEA was added. (H) Effects of equilin on cell proliferation of C4-2 cells. Equilin, 2.5 μM. (I) Effects of equilin on cell proliferation of C4-2 cells with or without UBE3D knocked out. Equilin, 5 μM; BCA, 5 μM. One-way ANOVA. (J) Effects of equilin on xenograft growth. C4-2 cells with or without UBE3D knocked out were used for xenograft assay. Mice were castrated and implanted with sustained-release DHEA pellets. BCA, 50 mg/kg/d; equilin, 50 mg/kg/d. (K) Tumor weights from xenograft assay. (L) Schema for 3βHSD1 regulation in aggressive prostate cancer and related treatment with equilin. Results are shown as mean ± SD. *P < 0.05, **P < 0.01 by 2-tailed Student’s t test unless otherwise stated.