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.
Highlights
Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway
To address the role of squalene epoxidase (SQLE) in PCa, we first confirmed that high SQLE expression is significantly associated with shorter biochemical relapse (BCR)-free survival in a TCGA dataset for primary PCa (PRAD primary; n = 430), as well as with higher preoperative prostate specific antigen (PSA) levels, overall Gleason scores, advanced tumour stages, and nodal-positive disease (Fig. 1a)
SQLE gene amplification was more frequent in metastatic lesions (24%) compared with primary tumours (7%) (Fig. S1a) and gene amplification was associated with enhanced expression in both primary and metastatic PCa (Fig. S1b), indicating that elevated SQLE expression might drive disease progression
Summary
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. 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. Prostate cancer (PCa) is a very heterogeneous disease regarding its clinical behaviour and likelihood of progression, and poses a global therapeutic challenge for clinicians[1]. Intratumoral steroidogenesis and ligand promiscuity provided the rationale for the development of therapeutic strategies that interfere with the androgen-receptor pathway in PCa. Inhibition of cytochrome P450 family 17 subfamily A member 1 (CYP17A1), an enzyme in the testosterone-synthesis pathway, by abiraterone acetate or the use of the nonsteroidal AR inhibitor enzalutamide have been evaluated for their efficacy in CRPC and are in clinical use[11, 12]. We show that blocking SQLE through miR-205 overexpression, genetic deletion, or competitive pharmacological inhibition significantly impaired growth in a panel of PCa cell lines, including abiraterone- and enzalutamide-resistant derivatives.
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