TET1 functions as a tumor suppressor in lung adenocarcinoma through epigenetic remodeling and immune modulation

Background: Ten-Eleven Translocation (TET1-3) dioxygenases oxidize 5-methylcytosine (5mC) in DNA to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), initiating DNA demethylation. Since their discovery in 2009, there have been contradictory reports regarding the roles of TET proteins in cancer. TET genes have been characterized as tumor suppressors because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, and TET2 gene mutations are common in hematological cancers. In contrast, TET1 was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. Results: In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression (OE) of TET1 in human lung adenocarcinoma (H441, H1975) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast, TET1 knockout (KO) accelerated lung adenocarcinoma cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed that TET1 overexpression was associated with increased prevalence of immune markers, primarily via activation of the TNF and NF-kB signaling pathways. Conversely, TET1 knockout in lung adenocarcinoma cells induced the expression of genes involved in cellular metabolism and cell growth. Conclusions: Our results are consistent with tumor suppressor role of TET1 gene in lung adenocarcinoma cells (H441, H1975) and reveal its possible role in activating antitumor immunity.