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Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer

Elahe A Mostaghel1,2

  • 1Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington. emostagh@fredhutch.org.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 12, 2018
PubMed

Insights

Castration-resistant prostate cancer involves loss of the HSD17B2 enzyme, crucial for androgen inactivation. Aberrant splicing creates inactive enzyme forms, driving tumor growth and offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Castration-resistant prostate cancer (CRPC) progression is linked to intratumoral androgens.
  • The androgen inactivation enzyme, HSD17B2, is often lost in CRPC.
  • Androgen signaling remains a key driver in advanced prostate cancer.

Purpose of the Study:

  • To investigate the role of HSD17B2 and alternative splicing in CRPC.
  • To explore aberrant splicing as a potential therapeutic strategy for prostate cancer.

Main Methods:

  • Analysis of HSD17B2 expression and alternative splicing in prostate cancer tissues.
  • Investigating the functional impact of HSD17B2 isoforms on enzyme activity and androgen levels.

Main Results:

  • Loss of functional HSD17B2 is a hallmark of CRPC.
  • Alternative splicing generates inactive HSD17B2 isoforms that destabilize the wild-type enzyme.
  • Aberrant splicing contributes to elevated intratumoral androgen levels, promoting tumor progression.

Conclusions:

  • Intratumoral androgen production, driven by aberrant splicing of HSD17B2, is critical for CRPC.
  • Targeting aberrant splicing represents a promising therapeutic avenue for castration-resistant prostate cancer.

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