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P53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance.

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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6419514 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Zhang Jixiang J Tan Peng P Guo Lei L Gong Jing J Ma Jingjing J Li Jia J Lee Minjung M Fang Shaohai S Jing Ji J Johnson Gavin G Sun Deqiang D Cao Wen-Ming WM Dashwood Roderick R Han Leng L Zhou Yubin Y Dong Wei-Guo WG Huang Yun Y

Oncogene 20181102 11

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 destabil ...[more]

PMID: 30390073

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Project description:BackgroundCancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy. We previously showed that activin-βC, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin α-KO mouse). This study aimed to identify the molecular mechanism by which activin-βC increases survival and abolishes cancer-associated cachexia in α-KO mice. We hypothesized that overexpression of activin-βC modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways.MethodsMale and female ActC++, α-KO, and α-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed.ResultsIncreased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the α-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- βC antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. α-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival.ConclusionOur findings show for the first time a specific effect of activin-βC on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-βC may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.

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P53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance.

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

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