Abstract 4460: TET1 over expression contributes to lung cancer malignancy

Abstract

Abstract Epigenetic alterations are a leading cause of lung carcinogenesis and malignancy. While the role of enzymes catalyzing cytosine-guanine (CpG) island methylation and chromatin modifications has been extensively studied, the role of the recently discovered demethylating enzymes represented by ten-eleven translocation methylcytosine dioxygenases (TETs) remains unknown. The goal of this study was to investigate the expression and functional significance of the TET1 gene in non-small cell lung cancer (NSCLC). QRT-PCR revealed 2- to 30-fold over expression of TET1 in 52% of squamous cell carcinoma (SCC) and 40% of adenocarcinoma (AdC) tumors compared to paired normal lung tissue. This result was validated using The Cancer Genome Atlas (TCGA) database with TET1 over expressed in 72% of SCCs and 53% of AdCs. Elevated levels of TET1 transcript were associated with increased protein levels in NSCLC cell lines compared to normal human bronchial epithelial cells (HBECs). A reporter assay analysis defined the promoter region critical for elevated transcription of the TET1 gene using lung cancer cell lines, and studies to identify the transcription factors underlying the increase in expression are underway. Transient knock down of TET1 expression in NSCLC cell lines caused global changes in the transcriptome, reduced cell proliferation, colony formation, and inhibited growth of tumor xenografts in nude mice. Cellular senescence mediated by p21 signaling and associated with β-galactosidase activation was identified as one mechanism underlying growth inhibition. This study suggests that TET1 may function as an oncogene contributing to the lung cancer malignant phenotype and thus, could serve as a potential new target for treatment. (Supported by R01 CA183296) Citation Format: Piotr Teodor Filipczak, Shuguang Leng, Carmen S. Tellez, Steven A. Belinsky. TET1 over expression contributes to lung cancer malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4460. doi:10.1158/1538-7445.AM2017-4460