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Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development
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- Xu, Qin (author)
- Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai 200031, Peoples R China.
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- Wang, Chao (author)
- Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai 200031, Peoples R China.
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- Zhou, Jia-Xin (author)
- Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai 200031, Peoples R China.
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- Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai 200031, Peoples R China Chinese Acad Sci, Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol,Shanghai Inst Biochem & C, Shanghai 200031, Peoples R China. (creator_code:org_t)
- 2022-02-02
- 2022
- English.
- In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:6
- Journal article (peer-reviewed)
Abstract
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- Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D-driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of beta-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targetingWnt signaling.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- epigenetic barriers
- DNA dioxygenases
- lung adenocarcinoma
- mouse models
- Wnt antagonizing genes
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Xu, Qin
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- Zhou, Jia-Xin
- Xu, Zhi-Mei
- Gao, Juan
- Sui, Pengfei
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- Walsh, Colum P.
- Ji, Hongbin
- Xu, Guo-Liang
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