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

Kalogirou C, Linxweiler J, Schmucker P, Snaebjornsson MT, Schmitz W, Wach S, Krebs M, Hartmann E, Puhr M, Müller A, Spahn M, Seitz AK, Frank T, Marouf H, Büchel G, Eckstein M, Kübler H, Eilers M, Saar M, Junker K, Röhrig F, Kneitz B, Rosenfeldt MT, Schulze A (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 12

Article Number: 5066

Journal Issue: 1

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.

Authors with CRIS profile

Markus Eckstein Institute of Pathology

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Kalogirou, C., Linxweiler, J., Schmucker, P., Snaebjornsson, M.T., Schmitz, W., Wach, S.,... Schulze, A. (2021). MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-25325-9

MLA:

Kalogirou, C., et al. "MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer." Nature Communications 12.1 (2021).

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