A phosphorylation switch controls androgen biosynthesis in prostate cancer
Yun Qiu
Yun Qiu
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e166499. https://doi.org/10.1172/JCI166499.
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Commentary

A phosphorylation switch controls androgen biosynthesis in prostate cancer

Abstract

Androgen biosynthesis enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) encoded by HSD3B1 has emerged as a potential driver for therapeutic resistance in prostate cancer. Patients with homozygous HSD3B1(1245C) inheritance are intrinsically more resistant to currently available androgen/androgen receptor–targeting (AR-targeting) drugs. In this issue of the JCI, Li et al. present data on the regulation of 3βHSD1 phosphorylation and activity by tyrosine kinase BMX. Inhibition of BMX activity by genetic or pharmacologic approaches blocked androgen biosynthesis in prostate cancer cells and inhibited tumor growth in preclinical xenograft models. The findings provide insights into mechanisms underlying castration resistance in prostate cancer and reveal a potential strategy to circumvent therapeutic resistance in patients with homozygous HSD3B1(1245C) inheritance.

Authors

Yun Qiu

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Figure 1

Targeting BMX regulation of androgen biosynthesis may circumvent therapeutic resistance in patients with prostate cancer.

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Targeting BMX regulation of androgen biosynthesis may circumvent therape...
Patients with prostate cancer who are homozygous for HSD3B1(1245C) rapidly develop resistance to ADT. 3βHSD1 promotes the conversion of DHEA to DHT, which interacts with ARs to promote tumor growth and enable prostate cancer progression to CRPC. Li et al. (4) revealed a step in the androgen biosynthesis pathway involving 3βHSD1 and the protein tyrosine kinase BMX. In the presence of DHEA, BMX phosphorylated 3βHSD1 at Y344. Phosphorylated 3βHSD1 formed an active dimer to facilitate the conversion of DHEA to AD, which is a weak androgen hormone and intermediate in the biosynthesis of T and estrogens. T is subsequently converted to more active DHT in prostate cancer cells. Notably, inhibition of BMX interfered with androgen conversion in prostate cancer cells and tumor tissue derived from patients. Patients with homozygous HSD3B1(1245C) inheritance may benefit from treatments that target the BMX/3βHSD1 axis. This axis may also have relevancy in other sex-hormone-related cancers, such as breast cancer.