2. Academic Validation
  3. METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions

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

  • Nat Commun. 2022 Oct 26;13(1):6350. doi: 10.1038/s41467-022-34209-5.
Yuanpei Li # 1,  Xiaoniu He # 1,  Xiao Lu 1,  Zhicheng Gong 2,  Qing Li 1,  Lei Zhang 1,  Ronghui Yang 3,  Chengyi Wu 1,  Jialiang Huang 1,  Jiancheng Ding 4,  Yaohui He 4,  Wen Liu 4,  Ceshi Chen 5,  Bin Cao 6,  Dawang Zhou 1,  Yufeng Shi 7,  Juxiang Chen 8,  Chuangui Wang 9,  Shengping Zhang 10,  Jian Zhang 11,  Jing Ye 12,  Han You 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102, Xiamen, China.
  • 2 Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, 214062, Wuxi, China.
  • 3 Department of Biochemistry and Molecular Biology, Capital Medical University, 100069, Beijing, China.
  • 4 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China.
  • 5 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China.
  • 6 Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102, Xiamen, China.
  • 7 Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, 200092, Shanghai, China.
  • 8 Department of Neurosurgery, Shanghai Changhai Hospital, Naval Medical University, 200433, Shanghai, China.
  • 9 The Biomedical Translational Research Institute, School of Life Sciences, Shandong University of Technology, 255049, Zibo, China.
  • 10 Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.
  • 11 The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032, Xi'an, China.
  • 12 Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, China.
  • 13 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102, Xiamen, China. hyou@xmu.edu.cn.
  • # Contributed equally.
PMID: 36289222 DOI: 10.1038/s41467-022-34209-5
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.

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