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Oncogene. 2018 Nov 2. doi: 10.1038/s41388-018-0524-5. [Epub ahead of print]

p53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance.

Author information

1
Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
2
Department of gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
3
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
4
Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
5
Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China, 310022.
6
Department of Molecular & Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX, 77843, USA.
7
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA. yzhou@ibt.tamhsc.edu.
8
Department of Medical Physiology, College of Medicine, Texas A&M University, Temple, TX, 76504, USA. yzhou@ibt.tamhsc.edu.
9
Department of gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China. dwg@whu.edu.cn.
10
Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA. yun.huang@ibt.tamhsc.edu.
11
Department of Molecular & Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX, 77843, USA. yun.huang@ibt.tamhsc.edu.

Abstract

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.

PMID:
30390073
DOI:
10.1038/s41388-018-0524-5

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