Journal Article

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

Rosenfeldt, M. T., Schmucker, P., Eckstein, M., Kalogirou, C., Schmitz, W., Kneitz, B., Hartmann, E., Frank, T., Snaebjornsson, M. T., Kübler, H., Büchel, G., Marouf, H., Saar, M., Schulze, A., Puhr, M., Linxweiler, J., Krebs, M., Eilers, M., Müller, A., Spahn, M., Junker, K., Wach, S., Röhrig, F., Seitz, A. K.

2021

Overview

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. Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/89 / 38/77 / 631/45/320 / 631/67 / 631/67/589 / 631/80/82 / 631/92/287 / 64/60 / 96/10 / 96/106 / Aged / Aged, 80 and over / Androgen receptors / Androgens / Animals / Antifungal agents / Antigens / Base Sequence / Biosynthesis / Cell Line, Tumor / Cell Proliferation - genetics / Cell Survival / Cholesterol / Cholesterol - biosynthesis / Cohort Studies / Computer Simulation / Disease Models, Animal / Down-Regulation - genetics / Drug Resistance, Neoplasm - genetics / Enzymes / Fungicides / Gene expression / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Lipid metabolism / Male / Mice / Mice, SCID / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / multidisciplinary / Neoplasm Invasiveness / Neoplasm Metastasis / Neoplasm Staging / Prostate cancer / 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 / Receptors, Androgen - metabolism / Science / Science (multidisciplinary) / Signal transduction / Squalene / Squalene epoxidase / Squalene Monooxygenase - antagonists & inhibitors / Squalene Monooxygenase - genetics / Squalene Monooxygenase - metabolism / Terbinafine / Terbinafine - pharmacology / Therapeutic targets / Transcriptional Activation - genetics / Tumors