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.

10-11 易位甲基胞嘧啶双加氧酶 2 (TET2) 突变引起的功能障碍在血液恶性肿瘤中被广泛报道。然而，TET2 在实体癌（包括结直肠癌 (CRC)）中的作用尚不清楚。在这里，我们发现 CRC 中的 TET2 功能障碍主要是由于核定位减少，并且 TET2 的核定位与患者更好的生存相关。为了探索潜在的机制，使用了 14 种永生化实体瘤细胞系和 12 种原代 CRC 细胞系。TET2 主要在细胞核中检测到，在 SW480 等细胞系中，它通过使RORA和SPARC去甲基化，诱导显着的 DNA 去甲基化并抑制细胞生长。而在像 SW620 这样的细胞系中，TET2 在细胞质中观察到，并且不影响 DNA 甲基化或细胞生长。免疫沉淀-质谱的进一步检查表明，β-连环蛋白的激活对于 TET2 的核定位和肿瘤抑制作用是不可或缺的。此外，同时使用β-catenin通路激活剂IM12和TET2激活剂维生素C，在低表达条件下增强TET2的作用，在体外和体内均观察到对癌症生长的协同抑制作用。总的来说，这些数据表明 β-catenin 介导的 TET2 核定位是实体瘤的重要治疗靶点。