Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.

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 genes. Here, we identify loss-of-function mutations of in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of -driven LUAD, we show that individual or combinational loss of genes markedly promotes tumor development. In this -mutant and -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-, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of -deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of -mutant lung cancer through targeting Wnt signaling.