Hypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells

Hailong Zhang, Xian Zhao, Yanmin Guo, Ran Chen, Jianfeng He, Lian Li, Zhe Qiang, Qianqian Yang, Xiaojia Liu, Caihu Huang, Runhui Lu, Jiayu Fang, Yingting Cao, Jiayi Huang, Yanli Wang, Jian Huang, Guo-Qiang Chen (), Jinke Cheng () and Jianxiu Yu ()
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Hailong Zhang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Xian Zhao: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Yanmin Guo: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Ran Chen: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jianfeng He: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Lian Li: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Zhe Qiang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Qianqian Yang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Xiaojia Liu: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Caihu Huang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Runhui Lu: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jiayu Fang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Yingting Cao: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jiayi Huang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Yanli Wang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jian Huang: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Guo-Qiang Chen: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jinke Cheng: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jianxiu Yu: State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with LUBAC, the linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution.

Date: 2021
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DOI: 10.1038/s41467-021-25739-5

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