Abstract
Elevated lipid metabolism is implicated in poor survival in ovarian cancer (OC) and other cancers; however, current lipogenesis-targeting strategies lack cancer cell specificity. Here, we identify a novel role of cystathionine beta-synthase (CBS), a sulphur amino acid metabolizing enzyme highly expressed in several ovarian cancer cell lines, in driving deregulated lipid metabolism in OC. We examined the role of CBS in regulation of triglycerides, cholesterol and lipogenic enzymes via the lipogenic transcription factors SREBP1 and SREBP2. CBS silencing attenuated the expression of number of key enzymes involved in lipid synthesis (FASN and ACC1). Additionally CBS abrogates lipid uptake in OC cells. Gene silencing of CBS or SREBPs abrogated cellular migration and invasion in OC, while ectopic expression of SREBPs can rescue phenotypic effects of CBS silencing by restoring cell migration and invasion. Mechanistically, CBS represses SREBP1 and SREBP2 at the transcription levels by modulating the transcription factor Sp1. We further established the roles of both CBS and SREBPs in regulating ovarian tumor growth in vivo. In orthotopic tumor models, CBS or SREBP silencing resulted in reduced tumor cells proliferation, blood vessels formation and lipid content. Hence, cancer-selective disruption of the lipid metabolism pathway is possible by targeting CBS and, at least for OC, promises a profound benefit.
Highlights
Epithelial ovarian carcinoma (EOC) is the fifth most common cause of cancer deaths among women in Western Europe and the U.S [1]
Nomura et al reported a specific lipid signature that was associated with overexpression of monoglyceride-lipase (MAGL), a lipase involved in releasing free fatty acids (FFAs) from triacylglycerols (TAGs) and its overexpression was found in highly aggressive cancers and its inhibition caused defects in cancer cell migration and tumor growth [14]
Having confirmed that cystathionine beta-synthase (CBS) and SREBPs are differentially overexpressed in ovarian cancer cell lines and possess significant lipid storage, we sought to examine the functional significance and the correlation of CBS and SREBPs in ovarian cancer
Summary
Epithelial ovarian carcinoma (EOC) is the fifth most common cause of cancer deaths among women in Western Europe and the U.S [1]. Nomura et al reported a specific lipid signature that was associated with overexpression of monoglyceride-lipase (MAGL), a lipase involved in releasing free fatty acids (FFAs) from triacylglycerols (TAGs) and its overexpression was found in highly aggressive cancers and its inhibition caused defects in cancer cell migration and tumor growth [14]. Taken together the aforesaid cues, possible involvement of H2S synthesizing enzyme CBS in SREBP mediated or independent cancer metabolic reprogramming are undeniable. Silencing CBS and SREBPs significantly inhibit tumor growth in pre-clinical orthotopic mouse models Taken together these results propose that CBS regulates lipid metabolism in ovarian cancer and provides a novel axis for ovarian cancer progression
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