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Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner

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Listed:
  • Yun-Qian Wang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Hao-Lian Wang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Jie Xu

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Juan Tan

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Lin-Na Fu

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Ji-Lin Wang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Tian-Hui Zou

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Dan-Feng Sun

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Qin-Yan Gao

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Ying-Xuan Chen

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Jing-Yuan Fang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

Abstract

Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1.

Suggested Citation

  • Yun-Qian Wang & Hao-Lian Wang & Jie Xu & Juan Tan & Lin-Na Fu & Ji-Lin Wang & Tian-Hui Zou & Dan-Feng Sun & Qin-Yan Gao & Ying-Xuan Chen & Jing-Yuan Fang, 2018. "Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02951-4
    DOI: 10.1038/s41467-018-02951-4
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    Cited by:

    1. Hao-Lian Wang & Yan Chen & Yun-Qian Wang & En-Wei Tao & Juan Tan & Qian-Qian Liu & Chun-Min Li & Xue-Mei Tong & Qin-Yan Gao & Jie Hong & Ying-Xuan Chen & Jing-Yuan Fang, 2022. "Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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