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Li, Yuanpei; He, Xiaoniu; Lu, Xiao; Gong, Zhicheng; Li, Qing; Zhang, Lei; Yang, Ronghui; Wu, Chengyi; Huang, Jialiang; Ding, Jiancheng; He, Yaohui; Liu, Wen; Chen, Ceshi; Cao, Bin; Zhou, Dawang; Shi, Yufeng; Chen, Juxiang; Wang, Chuangui; Zhang, Shengping; Zhang, Jian; Ye, Jing; You, Han
Nature communications, 10/2022, Letnik: 13, Številka: 1Journal Article
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 A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m 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 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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