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.
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These authors contributed equally to the work: Jixiang Zhang, Peng Tan, Lei Guo
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This work was supported by grants from Cancer Prevention and Research Institute of Texas (RR140053 to YH, to RP170660 to YZ, RR150085 to LH), the Innovation Award from American Heart Association (16IRG27250155 to YH), the John S. Dunn Foundation Collaborative Research Award (to YH), the Center for Translational Environmental Health Research (CTEHR) Seed Grant to YH, the National Institute of Health grants (R01HL134780 to YH, R01GM112003 to YZ), the Welch Foundation (BE-1913 to YZ), the American Cancer Society (RSG-18-043-01-LIB to YH, RSG-16-215-01-TBE to YZ), and by an allocation from the Texas A&M University start- up funds (YH).
YH and YZ conceived, directed and oversaw the project. JZ, JM and W-GD collected CRC samples, p53 mutation analysis and western blotting analysis. JL and DS analyzed the CRC western quantification data. JZ and LG performed the western blotting, doxorubicin / cisplatin treatment, gamma irradiation experiments. JZ and LG performed WST-1, colony-forming assays and quantitative real-time PCR analysis. JZ and ML performed the dot-blot assay. JZ and SF performed immunofluorescent staining. JZ generated majority cell lines used in this study. TP provided cell lines lacking autophagosome components and cell cycle blocking experiments. JG and LH performed the mutational analysis in AML patients. GJ and RD provided colon cancer cell lines. JJ, W-MC, RD and W-GD provided intellectual inputs. YH and YZ wrote the manuscript with all the other authors participating in discussion, data interpretation and manuscript editing.