Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target

Abstract

Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase () as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet-induced HCC. exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP). Increased expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. increased the NADP/NADPH (reduced form of NADP) ratio, which triggered a cascade of events involving oxidative stress-induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration-approved antifungal drug targeting, markedly inhibited -induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC.

Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling

“…Upregulation of the metabolic genes ( ALDH18A1 , CAD , CHKA , POLD4 , PSPH , SQLE ) may function in accelerating cellular metabolism. Of note, SQLE (squalene epoxidase) encodes a rate-limiting enzyme in cholesterol biosynthesis and exerts oncogenic roles in cancers 32 – 34 . Our team has recently revealed that upregulation of SQLE plays an important oncogenic role in driving NAFLD-HCC 32 .…”

“…Of note, SQLE (squalene epoxidase) encodes a rate-limiting enzyme in cholesterol biosynthesis and exerts oncogenic roles in cancers 32 – 34 . Our team has recently revealed that upregulation of SQLE plays an important oncogenic role in driving NAFLD-HCC 32 . CFD encodes human adipsin that functions as an adipokine and regulates insulin secretion 35 .…”

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

“…Consistently, in hepatocellular carcinoma induced by non-alcoholic fatty liver disease, SQLE expression is dramatically elevated. Enhanced levels of SQLE cause downregulation of PTEN expression and subsequent activation of Akt signalling, thus increasing CE levels and facilitating cancer development 64 . In summary, whereas oncogenes promote active cholesterol biosynthesis and facilitate tumour growth, tumour suppressors antagonize this overactivated state and maintain cholesterol homeostasis (Fig.…”

Role of de novo cholesterol synthesis enzymes in cancer

“…In human NAFLD-induced HCC and HCC, SQLE was overexpressed and its expression was associated with poor patient outcomes. Terbinafine, an SQLE-targeting drug, markedly inhibited SQLE-induced cell growth in NAFLD-induced HCC and HCC cells and attenuated tumor development in xenograft models and SQLE transgenic mice 66,67 . These findings are consistent with observations from Stopsack et al and Brown and his colleagues.…”