Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
Department of gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
Oncogene. 2019 Mar;38(11):1905-1919. doi: 10.1038/s41388-018-0524-5. Epub 2018 Nov 2.
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.
肿瘤细胞中 p53 的失活常常导致化疗耐药，这对癌症治疗构成了长期的挑战。在这里，我们揭示了 TET2 在介导结肠癌中 p53 缺失诱导的化疗耐药中的一个先前未被认识的作用。在 p53 缺失的结肠癌细胞中敲除 TET2 会增强 DNA 损伤并恢复化疗敏感性。通过采用药物抑制和基因敲除相结合的双管齐下的方法，我们发现 p53 通过促进其自噬降解在蛋白质水平上使 TET2 不稳定。在分子水平上，我们进一步揭示了 TET2 和 p53 之间的物理关联，促进了 TET2 的核质穿梭，并将其募集到自噬体进行降解。我们的研究揭示了在抗癌治疗过程中 TET2 和 p53 之间的功能相互作用。我们的发现为靶向 TET2 以克服与突变 p53 肿瘤相关的化疗耐药提供了依据。
