SIGNIFICANCE: These studies identify TET1 as an oncogene in lung cancer whose gain of function following loss of p53 may be exploited by targeted therapy-induced senescence.<i>See related commentary by Kondo, p. 1751</i>.
Depletion of TET1 was synergistic with classical antitumor drugs, such as cisplatin or doxorubicin, providing an attractive rationale for targeted therapies against TET1 combined with antitumor drugs in patients with p53-mutant lung cancer.<i>See related article by Filipczak et al., p. 1758</i>.
Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer.
Mining gene expression data of lung cancer cell lines identified additional TSGs suppressed by KRAS signaling whose expression was restored by inhibition of miR-29b and re-expression of TET1.
Collectively, these findings suggest that Tet1 expression plays a critical role in metastasis of lung cancer cells by suppression of invasion and epithelial-mesenchymal transition (EMT).
Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells.