METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions

Yuanpei Li, Xiaoniu He, Xiao Lu, Zhicheng Gong, Qing Li, Lei Zhang, Ronghui Yang, Chengyi Wu, Jialiang Huang, Jiancheng Ding, Yaohui He, Wen Liu, Ceshi Chen, Bin Cao, Dawang Zhou, Yufeng Shi, Juxiang Chen, Chuangui Wang, Shengping Zhang, Jian Zhang, Jing Ye and Han You ()
Additional contact information
Yuanpei Li: Xiamen University
Xiaoniu He: Xiamen University
Xiao Lu: Xiamen University
Zhicheng Gong: Affiliated Hospital of Jiangnan University
Qing Li: Xiamen University
Lei Zhang: Xiamen University
Ronghui Yang: Capital Medical University
Chengyi Wu: Xiamen University
Jialiang Huang: Xiamen University
Jiancheng Ding: Xiamen University
Yaohui He: Xiamen University
Wen Liu: Xiamen University
Ceshi Chen: Chinese Academy of Sciences
Bin Cao: Xiamen University
Dawang Zhou: Xiamen University
Yufeng Shi: Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University
Juxiang Chen: Naval Medical University
Chuangui Wang: Shandong University of Technology
Shengping Zhang: Shanghai Jiao Tong University School of Medicine
Jian Zhang: Fourth Military Medical University
Jing Ye: Fourth Military Medical University
Han You: Xiamen University

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m6A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m6A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m6A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.

Date: 2022
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DOI: 10.1038/s41467-022-34209-5

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