Chakraborty Prabir K, Xiong Xunhao, Mustafi Soumyajit Banerjee, Saha Sounik, Dhanasekaran Danny, Mandal Nawajes A, McMeekin Scott, Bhattacharya Resham, Mukherjee Priyabrata
Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oncotarget. 2015 Nov 10;6(35):37367-84. doi: 10.18632/oncotarget.5424.
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.
脂质代谢升高与卵巢癌（OC）及其他癌症的不良预后有关；然而，目前针对脂肪生成的策略缺乏癌细胞特异性。在此，我们发现了胱硫醚β-合酶（CBS）——一种在多种卵巢癌细胞系中高表达的硫氨基酸代谢酶——在驱动OC中失调的脂质代谢方面的新作用。我们通过脂肪生成转录因子SREBP1和SREBP2研究了CBS在调节甘油三酯、胆固醇和脂肪生成酶中的作用。CBS沉默减弱了参与脂质合成的多种关键酶（FASN和ACC1）的表达。此外，CBS消除了OC细胞中的脂质摄取。CBS或SREBPs的基因沉默消除了OC中的细胞迁移和侵袭，而SREBPs的异位表达可通过恢复细胞迁移和侵袭来挽救CBS沉默的表型效应。从机制上讲，CBS通过调节转录因子Sp1在转录水平上抑制SREBP1和SREBP2。我们进一步确定了CBS和SREBPs在体内调节卵巢肿瘤生长中的作用。在原位肿瘤模型中，CBS或SREBP沉默导致肿瘤细胞增殖、血管形成和脂质含量减少。因此，通过靶向CBS来选择性破坏脂质代谢途径是可能的，至少对于OC来说，有望带来巨大益处。
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