The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis

• Published in: Nature communications 2024-08, Vol.15 (1), p.7455-18, Article 7455
• Main Authors: Zhao, Wentao, Ouyang, Cong, Zhang, Liang, Wang, Jinyang, Zhang, Jiaojiao, Zhang, Yan, Huang, Chen, Xiao, Qiao, Jiang, Bin, Lin, Furong, Zhang, Cixiong, Zhu, Mingxia, Xie, Changchuan, Huang, Xi, Zhang, Bingchang, Zhao, Wenpeng, He, Jiawei, Chen, Sifang, Liu, Xiyao, Lin, Donghai, Li, Qinxi, Wang, Zhanxiang
• Format: Article
• Language: English
• Subjects: 13/109; 631/67/1922; 631/67/2327; 82/1; 82/29; 82/58; Acetic acid; Acetyl Coenzyme A - metabolism; Animals; ATP; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Chemical synthesis; CSK Tyrosine-Protein Kinase - genetics; CSK Tyrosine-Protein Kinase - metabolism; Cytosol; Disease Progression; Fatty acids; Fatty Acids - biosynthesis; Fatty Acids - metabolism; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioma; Glioma cells; Humanities and Social Sciences; Humans; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Kinases; Malignancy; Mice; Mice, Nude; multidisciplinary; NADP - metabolism; Oncogenes; Phosphorylation; Proto-Oncogene Mas; Science; Science (multidisciplinary); Src protein; src-Family Kinases - genetics; src-Family Kinases - metabolism; Substrates; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51444-0

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.