肿瘤的发展涉及细胞增长（质量积累）和细胞增殖，是由多个信号通路的相互作用所调控的一个复杂过程。TET2主要作为DNA双氧酶，通过氧化DNA中的5mC来调节基因表达和生物功能，然而它是否在调控细胞增长中发挥作用尚不清楚。在这里，我们展示了TET2抑制mTORC1信号通路，一个主要的生长调控器，从而抑制细胞增长并促进自噬。机制上，TET2作为5mC的“橡皮擦”通过mRNA氧化作用，消除了YBX1-HuR结合，并促进尿素循环酶mRNA的降解，从而负调节尿素循环和精氨酸产生，抑制mTORC1信号通路。因此，TET2缺乏的肿瘤细胞对mTORC1的抑制更敏感。我们的结果揭示了TET2在抑制mTORC1信号传导和抑制细胞生长方面的新功能，将TET2介导的mRNA氧化与细胞代谢和细胞生长调控相联系。这些发现表明mTORC1抑制可能作为治疗TET2缺陷肿瘤的一种潜在方法。© 2023. 中国科学院细胞科学卓越中心。

Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1-HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.© 2023. Center for Excellence in Molecular Cell Science, CAS.