Epigenetic Suppression of the T-box Subfamily 2 () in Human Non-Small Cell Lung Cancer.

Int J Mol Sci

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Riad El Solh 1107 2020 Beirut, Lebanon.

Published: March 2019

(1) The subfamily of transcription factors (s 2, 3, 4 and 5) are markedly down-regulated in human non-small cell lung cancer (NSCLC) and exert tumor suppressor effects in lung malignancy. Yet, mechanisms underlying suppressed expression of the subfamily in NSCLC are elusive. Here, we interrogated probable epigenetic mechanisms in suppressed expression of the subfamily in human NSCLC. (2) subfamily gene expression and methylation levels in NSCLC and normal lung tissues were surveyed using publicly available RNA-sequence and genome-wide methylation datasets. Methylation β-values of the four genes were statistically compared between NSCLCs and normal lung tissues, correlated with gene expression levels, and interrogated with clinicopathological variables. Expression and methylation levels of s were quantified in NSCLC cells using real-time PCR and methylation-specific PCR assays, respectively. Effects of the DNA methyltransferase inhibitor 5-azacytidine (Aza) on subfamily expression were assessed in NSCLC cells. Impact of subfamily expression on Aza-treated cells was evaluated by RNA interference. (3) All four s were significantly hypermethylated in NSCLCs relative to normal lung tissues ( < 0.05). Methylation β-values of the genes, with exception of , were significantly inversely correlated with corresponding mRNA expression levels ( < 0.05). We found no statistically significant differences in hypermethylation levels of the subfamily by clinicopathological features including stage and tobacco history. Expression levels of the genes were overall suppressed in NSCLC cells relative to normal alveolar cells. Members of the subfamily were significantly hypermethylated in all tested NSCLC cell lines relative to normal alveolar cells. Treatment with Aza induced the expression of the subfamily concomitant with NSCLC cell growth inhibition. Further, simultaneous knockdown of the four genes markedly reduced anti-growth effects of Aza in NSCLC cells. (4) Our study sheds light on new epigenetic profiles in the molecular pathogenesis of human NSCLC.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429281PMC
http://dx.doi.org/10.3390/ijms20051159DOI Listing

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