Tumor cells with p53 inactivation frequently exhibit chemotherapy resistance, which poses a long-standing challenge to cancer treatment. Here we unveiled a previously unrecognized role of TET2 in mediating p53-loss induced chemotherapy resistance in colon cancer. Deletion of TET2 in p53-null colon cancer cells enhanced DNA damage and restored chemotherapy sensitivity. By taking a two-pronged approach that combined pharmacological inhibition with genetic depletion, we discovered that p53 destabilized TET2 at the protein level by promoting its autophagic degradation. At the molecular level, we further revealed a physical association between TET2 and p53 that facilitated the nucleoplasmic shuttling of TET2, as well as its recruitment to the autophagosome for degradation. Our study has unveiled a functional interplay between TET2 and p53 during anti-cancer therapy. Our findings establish the rationale for targeting TET2 to overcome chemotherapy resistance associated with mutant p53 tumors.

中文翻译：

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TET2 的 p53 依赖性自噬降解调节癌症治疗抵抗。

p53 失活的肿瘤细胞经常表现出化疗耐药性，这对癌症治疗提出了长期挑战。在这里，我们揭示了 TET2 在介导 p53 缺失诱导的结肠癌化疗耐药中的先前未被认识的作用。在 p53-null 结肠癌细胞中删除 TET2 会增强 DNA 损伤并恢复化疗敏感性。通过采取将药理学抑制与遗传耗竭相结合的双管齐下的方法，我们发现 p53 通过促进 TET2 的自噬降解在蛋白质水平上破坏了 TET2 的稳定性。在分子水平上，我们进一步揭示了 TET2 和 p53 之间的物理关联，这促进了 TET2 的核质穿梭，以及其募集到自噬体进行降解。我们的研究揭示了抗癌治疗期间 TET2 和 p53 之间的功能相互作用。我们的研究结果确立了靶向 TET2 以克服与突变 p53 肿瘤相关的化疗耐药性的基本原理。