Role of cystathionine beta synthase in lipid metabolism in ovarian cancer

Prabir K. Chakraborty, Xunhao Xiong, Soumyajit Banerjee Mustafi, Sounik Saha, Danny Dhanasekaran, Nawajes A. Mandal, Scott McMeekin, Resham Bhattacharya, Priyabrata Mukherjee

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37367-37384
Number of pages18
JournalOncotarget
Volume6
Issue number35
DOIs
StatePublished - 2015

Keywords

  • CBS
  • Lipid metabolism
  • Ovarian cancer
  • SREBP

ASJC Scopus subject areas

  • Oncology

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    Chakraborty, P. K., Xiong, X., Mustafi, S. B., Saha, S., Dhanasekaran, D., Mandal, N. A., McMeekin, S., Bhattacharya, R., & Mukherjee, P. (2015). Role of cystathionine beta synthase in lipid metabolism in ovarian cancer. Oncotarget, 6(35), 37367-37384. https://doi.org/10.18632/oncotarget.5424