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

Author

Listed:
  • Wentao Zhao

    (Xiamen University
    Xiamen University)

  • Cong Ouyang

    (Xiamen University)

  • Liang Zhang

    (Xiamen University)

  • Jinyang Wang

    (Xiamen University)

  • Jiaojiao Zhang

    (Xiamen University)

  • Yan Zhang

    (Xiamen University)

  • Chen Huang

    (Xiamen University)

  • Qiao Xiao

    (Xiamen University)

  • Bin Jiang

    (Xiamen University)

  • Furong Lin

    (Xiamen University)

  • Cixiong Zhang

    (Xiamen University)

  • Mingxia Zhu

    (Xiamen University)

  • Changchuan Xie

    (Xiamen University)

  • Xi Huang

    (Xiamen University)

  • Bingchang Zhang

    (Xiamen University)

  • Wenpeng Zhao

    (Xiamen University)

  • Jiawei He

    (Xiamen University)

  • Sifang Chen

    (Xiamen University)

  • Xiyao Liu

    (Xiamen University)

  • Donghai Lin

    (Xiamen University)

  • Qinxi Li

    (Xiamen University)

  • Zhanxiang Wang

    (Xiamen University)

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.

Suggested Citation

  • 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 & Bingch, 2024. "The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51444-0
    DOI: 10.1038/s41467-024-51444-0
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    References listed on IDEAS

    as
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