Role of cystathionine beta synthase in lipid metabolism in ovarian cancer
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Prabir K. Chakraborty1, Xunhao Xiong1, Soumyajit Banerjee Mustafi2, Sounik Saha1, Danny Dhanasekaran3, Nawajes A. Mandal4, Scott McMeekin2,5, Resham Bhattacharya2,5, Priyabrata Mukherjee1,5
1Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
2Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
3Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
4Dean A. McGee Eye Institute, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
5Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
Priyabrata Mukherjee, e-mail: [email protected]
Keywords: CBS, lipid metabolism, SREBP, ovarian cancer
Received: June 10, 2015 Accepted: September 24, 2015 Published: October 06, 2015
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.
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