TET2基因突变导致其功能失调被广泛报道在血液系统恶性肿瘤中已有的研究。然而，关于TET2在实体肿瘤中（包括结直肠癌）的作用还不清楚。本研究发现，TET2在结直肠癌中的功能失常主要是由于其核定位的减少，而TET2的核定位与患者生存率良好相关。为了探索其潜在机制，我们使用了14株经过免疫细胞化学固定的实体肿瘤细胞株和12株原发性结直肠癌细胞株。结果显示，TET2主要在细胞核中检测到，并且通过对SW480等细胞株中的RORA和SPARC进行去甲基化作用来显著抑制DNA甲基化和细胞生长。而在SW620等细胞株中，TET2观察到主要位于细胞质中，并且不影响DNA甲基化和细胞生长。进一步的免疫沉淀-质谱检测表明，β-连环蛋白激活是TET2的核定位和抑制肿瘤作用的必要条件。此外，β-连环蛋白信号通路激活剂IM12和TET2激活剂维生素C同时使用以加强TET2在低表达条件下的效果，结果观察到它们在体外和体内对肿瘤生长的协同抑制效果。综上所述，这些数据表明β-连环蛋白介导的TET2的核定位是实体肿瘤的一个重要治疗靶点。© 2023. 作者。

Mutation-induced malfunction of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is widely reported in haematological malignancies. However, the role of TET2 in solid cancers, including colorectal cancer (CRC), is unclear. Here, we found that TET2 malfunction in CRC is mostly due to decreased nuclear localization and that nuclear localization of TET2 is correlated with better survival of patients. To explore the underlying mechanisms, 14 immortalized solid tumour cell lines and 12 primary CRC cell lines were used. TET2 was mostly detected in the nucleus, and it induced significant DNA demethylation and suppressed cell growth by demethylating RORA and SPARC in cell lines like SW480. While in cell lines like SW620, TET2 was observed in the cytosol and did not affect DNA methylation or cell growth. Further examination with immunoprecipitation-mass spectrometry illustrated that β-catenin activation was indispensable for the nuclear localization and tumour suppression effects of TET2. In addition, the β-catenin pathway activator IM12 and the TET2 activator vitamin C were used simultaneously to enhance the effects of TET2 under low-expression conditions, and synergistic inhibitory effects on the growth of cancer were observed both in vitro and in vivo. Collectively, these data suggest that β-catenin-mediated nuclear localization of TET2 is an important therapeutic target for solid tumours.© 2023. The Author(s).