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 Kras G12D-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 β-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 targeting Wnt signaling.
|Number of pages||12|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2 Feb 2022|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank L.-A. Xu and C.-H. Wang for assistance with quantitative mass spectrometry analysis and H.-Q. Dai, X.-K. Han, and J. Zhang for technical help. We also thank X. Sun, Y.-J. Shi, S.-Y. Sun, J. Huang, X.-Q. Kong, L.-L. Shen, and G.-N. Liang for insightful comments. This work was supported by the National Key Research and Development Program of China (Grant 2017YFA0102701 to G.-L.X., Grant 2017YFA0505501 to H.J., and Grant 2020YFA0803300 to H.J.), the National Natural Science Foundation of China (Grants 31830018 and 31430049 to G.-L.X. and Grants 31621003, 81872312, 82030083, and 82011540007 to H.J.), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB19010102 to G.-L.X. and Grant XDB19020201 to H.J.), the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences (Grant ZDBS-LY-SM006 to H.J.), the International Cooperation Project of Chinese Academy of Sciences (Grant 153D31KYSB20190035 to H.J.), and the Newton International Exchange Award (IE160973 to G.-L.X. and C.P.W.).
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- DNA dioxygenases
- Wnt antagonizing genes
- Mouse models
- Epigenetic barriers
- Lung adenocarcinoma