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bioRxiv · 10.1101/2024.10.31.621362

TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

Rahim, A.·Ruis, B.·Rajczewski, A. T.·Kruk, M.·Tretyakova, N.
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Abstract

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. The three proteins share significant sequence homology and catalyze the same chemical reaction utilizing alpha-ketoglutarate cofactor and non-heme iron to oxidize the methyl group of 5mC. 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 suppressor genes because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, and TET2 gene mutations are common in hematological cancers. However, TET1 was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression of TET1 in human lung adenocarcinoma (H441) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast, TET1 knockout in lung adenocarcinoma accelerated cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed that TET1 overexpression was associated with overexpression of immune markers, primarily via activation of TNF and NF-kB signaling pathways. TET1 knockout in lung adenocarcinoma cells induces the expression of genes involved in cellular metabolism and cell growth. Our results are consistent with a tumor suppressor role of TET1 gene in lung adenocarcinoma and reveal its role in activating antitumor immunity.

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Rahim, A., Ruis, B., Rajczewski, A. T., Kruk, M., Tretyakova, N.. 2024-11-03. TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation. https://doi.org/10.1101/2024.10.31.621362

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