Methyltransferase-like 3 (METTL3)是哺乳动物细胞N6-腺苷甲基转移酶复合物的催化亚基，负责对mRNA进行N6-甲基腺苷（m6A）修饰。虽然METTL3在多种癌症中表达增加，但其调控机制尚不清楚。我们探究了肽酰脯氨酸顺反异构酶NIMA交互蛋白1（PIN1）在METTL3稳定性和m6A修饰的mRNA中的调节作用。PIN1与METTL3相互作用，并防止其泛素依赖性蛋白酶体和溶酶体降解。它稳定了METTL3，从而增加了转录共激活因子与PDZ结合蛋白（TAZ）和表皮生长因子受体（EGFR）mRNA的m6A修饰，加强了它们的翻译效率。PIN1基因突变改变了TAZ和EGFR mRNA从多聚体向单聚体的分布。MEK1/2激酶和PIN1抑制剂使METTL3不稳定，阻碍了乳腺癌细胞的增殖，并在G0/G1期诱导细胞周期停滞。METTL3基因敲除降低了PIN1过表达引起的MCF7细胞克隆形成，并在4T1细胞的原位小鼠模型中促进了肿瘤生长。在临床上，METTL3表达随着肿瘤进展显著增加，并与乳腺癌组织中的PIN1表达呈正相关。因此，PIN1在mRNA翻译中发挥了调节作用，而PIN1/METTL3轴可能是乳腺癌的一种替代治疗靶点。©2023作者，独家许可Springer Nature Limited发表。

Methyltransferase-like 3 (METTL3) is the catalytic subunit of the N6-adenosine methyltransferase complex responsible for N6-methyladenosine (m6A) modification of mRNA in mammalian cells. Although METTL3 expression is increased in several cancers, the regulatory mechanisms are unclear. We explored the regulatory roles of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in METTL3 stability and m6A modification of mRNA. PIN1 interacted with METTL3 and prevented its ubiquitin-dependent proteasomal and lysosomal degradation. It stabilized METTL3, which increased the m6A modification of transcriptional coactivator with PDZ-binding motif (TAZ) and epidermal growth factor receptor (EGFR) mRNA, resulting in their efficient translation. PIN1 knockout altered the distribution of TAZ and EGFR mRNA from polysomes into monosomes. Inhibition of MEK1/2 kinases and PIN1 destabilized METTL3, which impeded breast cancer cell proliferation and induced cell cycle arrest at the G0/G1 phases. METTL3 knockout reduced PIN1 overexpression-induced colony formation in MCF7 cells and enhanced tumor growth in 4T1 cells in an orthotopic mouse model. In clinical settings, METTL3 expression significantly increased with tumor progression and was positively correlated with PIN1 expression in breast cancer tissues. Thus, PIN1 plays a regulatory role in mRNA translation, and the PIN1/METTL3 axis may be an alternative therapeutic target in breast cancer.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.