AR Signaling in Prostate Cancer Regulates a Feed-Forward Mechanism of Androgen Synthesis by Way of HSD3B1 Upregulation.

Endocrinology
Daniel HettelNima Sharifi

Abstract

3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation. Generally, it is thought that intratumoral androgen synthesis is upregulated after gonadal testosterone deprivation, enabling development of castration-resistant prostate cancer. Given its critical role in extragonadal androgen synthesis, we sought to directly interrogate the transcriptional regulation of HSD3B1 in multiple metastatic prostate cancer cell models. Surprisingly, we found that VCaP, CWR22Rv1, LNCaP, and LAPC4 models demonstrate induction of HSD3B1 upon androgen stimulation for approximately 72 hours, followed by attenuation around 120 hours. 3βHSD1 protein levels mirrored transcriptional changes in models harboring variant (LNCaP) and wild-type (LAPC4) HSD3B1, and in these models androgen induction of HSD3B1 is abrogated via enzalutamide treatment. Androgen treatment increased flux from [3H]-dehydro...Continue Reading

References

Jul 15, 2005·JAMA : the Journal of the American Medical Association·Nima SharifiWilliam L Dahut
Dec 23, 2008·Molecular and Cellular Endocrinology·Krishan K RasiahVanessa M Hayes
Jan 12, 2011·Nature Biotechnology·James T RobinsonJill P Mesirov
Jul 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kai-Hsiung ChangNima Sharifi
Mar 11, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Katelyn PowellSreenivasa R Chinni
Apr 9, 2017·Cold Spring Harbor Perspectives in Medicine·Charles DaiNima Sharifi

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Citations

Oct 16, 2019·Annual Review of Medicine·Richard J Auchus, Nima Sharifi
Nov 6, 2018·International Journal of Endocrinology·Javier Menéndez-Menéndez, Carlos Martínez-Campa
Aug 22, 2018·International Urology and Nephrology·Zhonglin CaiHongjun Li
May 16, 2020·Molecular and Cellular Endocrinology·Simona NanniAntonella Farsetti

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