MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Nat Commun. 2021 Aug 20;12(1):5066. doi: 10.1038/s41467-021-25325-9.

Abstract

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Survival
  • Cholesterol / biosynthesis*
  • Cohort Studies
  • Computer Simulation
  • Disease Models, Animal
  • Down-Regulation / genetics*
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptors, Androgen / metabolism
  • Squalene Monooxygenase / antagonists & inhibitors*
  • Squalene Monooxygenase / genetics
  • Squalene Monooxygenase / metabolism
  • Terbinafine / pharmacology
  • Transcriptional Activation / genetics

Substances

  • MIRN205 microRNA, human
  • MicroRNAs
  • Receptors, Androgen
  • Cholesterol
  • Squalene Monooxygenase
  • Prostate-Specific Antigen
  • Terbinafine