MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration

Jianxiong Chen, Shiyu Duan, Yulu Wang, Yuping Ling, Xiaotao Hou, Sijing Zhang, Xunhua Liu, Xiaoli Long, Jiawen Lan, Miao Zhou, Huimeng Xu, Haoxuan Zheng () and Jun Zhou ()
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Jianxiong Chen: Southern Medical University
Shiyu Duan: Southern Medical University
Yulu Wang: Southern Medical University
Yuping Ling: Southern Medical University
Xiaotao Hou: Southern Medical University
Sijing Zhang: Southern Medical University
Xunhua Liu: Southern Medical University
Xiaoli Long: Southern Medical University
Jiawen Lan: Southern Medical University
Miao Zhou: Southern Medical University
Huimeng Xu: Southern Medical University
Haoxuan Zheng: Southern Medical University
Jun Zhou: Southern Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Metabolic remodeling is a strategy for tumor survival under stress. However, the molecular mechanisms during the metabolic remodeling of colorectal cancer (CRC) remain unclear. Melanocyte proliferating gene 1 (MYG1) is a 3′−5′ RNA exonuclease and plays a key role in mitochondrial functions. Here, we uncover that MYG1 expression is upregulated in CRC progression and highly expressed MYG1 promotes glycolysis and CRC progression independent of its exonuclease activity. Mechanistically, nuclear MYG1 recruits HSP90/GSK3β complex to promote PKM2 phosphorylation, increasing its stability. PKM2 transcriptionally activates MYC and promotes MYC-medicated glycolysis. Conversely, c-Myc also transcriptionally upregulates MYG1, driving the progression of CRC. Meanwhile, mitochondrial MYG1 on the one hand inhibits oxidative phosphorylation (OXPHOS), and on the other hand blocks the release of Cyt c from mitochondria and inhibits cell apoptosis. Clinically, patients with KRAS mutation show high expression of MYG1, indicating a high level of glycolysis and a poor prognosis. Targeting MYG1 may disturb metabolic balance of CRC and serve as a potential target for the diagnosis and treatment of CRC.

Date: 2024
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DOI: 10.1038/s41467-024-49221-0

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