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

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	METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions
	Li, YP; He, XN; Lu, X; Gong, ZC; Li, Q; Zhang, L; Yang, RH; Wu, CY; Huang, JL; Ding, JC; He, YH; Liu, W; Chen, CS; Cao, B; Zhou, DW; Shi, YF; Chen, JX; Wang, CG; Zhang, SP; Zhang, J; Ye, J; You, H
	2022
发表期刊	NATURE COMMUNICATIONS
卷号	13 期号:1
摘要	METTL3 catalyzes mRNA m(6)A deposition. The authors identify an acetylation-mediated regulation of METTL3 subcellular localization and compartment-specific functions, a process that is fine-tuned by anti-inflammatory and pro-inflammatory signals, which ultimately determine breast cancer metastasis. 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 m(6)A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m(6)A 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 m(6)A 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.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13695
专题	科研部门_肿瘤生物学（陈策实）
推荐引用方式 GB/T 7714	Li, YP,He, XN,Lu, X,et al. METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions[J]. NATURE COMMUNICATIONS,2022,13(1).
APA	Li, YP.,He, XN.,Lu, X.,Gong, ZC.,Li, Q.,...&You, H.(2022).METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions.NATURE COMMUNICATIONS,13(1).
MLA	Li, YP,et al."METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions".NATURE COMMUNICATIONS 13.1(2022).

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