The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis
Wentao Zhao, Cong Ouyang, Liang Zhang, Jinyang Wang, Jiaojiao Zhang, Yan Zhang, Chen Huang, Qiao Xiao, Bin Jiang, Furong Lin, Cixiong Zhang, Mingxia Zhu, Changchuan Xie, Xi Huang, Bingchang Zhang, Wenpeng Zhao, Jiawei He, Sifang Chen, Xiyao Liu, Donghai Lin, Qinxi Li, Zhanxiang Wang, Qinxi Li, Zhanxiang Wang
Abstract
Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition. Fatty acid synthesis has been reported to promote glioblastoma. Here, the authors show that the tyrosine kinase c-SRC phosphorylates both acetyl-CoA synthetase ACSS2 and ATP-citrate lyase ACLY, to increase acetyl-CoA and NADPH production for fatty acid synthesis to support glioblastoma progression.