Abstract
DNA methylation is an essential epigenetic marker associated with the silencing of gene expression. Although various genome-wide studies revealed aberrantly methylated gene targets as molecular biomarkers for early detection, the survival rate of lung cancer patients is still poor. In order to identify methylation-driven biomarkers, genome-wide changes in DNA methylation and differential expression in 32 pairs of lung adenocarcinoma and adjacent normal lung tissue in non-smoking women were examined. This concurrent analysis identified 21 negatively correlated probes (r ≤ −0.5), corresponding to 17 genes. Examining the endogenous expression in lung cancer cell lines, five of the genes were found to be significantly down-regulated. Furthermore, in tumor cells alone, 5-aza-2′-deoxycytidine treatment increased the expression levels of STXBP6 in a dose dependent manner and pyrosequencing showed higher percentage of methylation in STXBP6 promoter. Functional analysis revealed that overexpressed STXBP6 in A549 and H1299 cells significantly decreased cell proliferation, colony formation, and migration, and increased apoptosis. Finally, significantly lower survival rates (P < 0.05) were observed when expression levels of STXBP6 were low. Our results provide a basis for the genetic etiology of lung adenocarcinoma by demonstrating the possible role of hypermethylation of STXBP6 in poor clinical outcomes in lung cancer patients.
Highlights
A wide variety of risk factors, such as genetic, epigenetic, and environmental factors, may cause lung cancer
Genome-wide expression (41,789 probes) and DNA methylation profiling (27,578 probes) in 32 pairs of tumor and adjacent normal tissues were analyzed in non-smoking women with lung adenocarcinoma (Table S2)
These findings indicate that epigenetic changes in STXBP6 may be useful for predicting the prognosis of patients with lung adenocarcinoma
Summary
A wide variety of risk factors, such as genetic, epigenetic, and environmental factors, may cause lung cancer. The role of methylation in the tumorigenesis of lung adenocarcinoma and association with prognosis in Taiwan remains largely unknown. For this reason, we performed an integrated analysis of gene expression and DNA methylation status to find novel epigenetic markers of lung cancer. We performed an integrated analysis of gene expression and DNA methylation status to find novel epigenetic markers of lung cancer With this approach, we identified STXBP6, whose expression was significantly repressed by methylation, affected cellular function in cancer cell lines, and was associated with overall survival. There are no studies revealing its biological role in association with lung cancer and its epigenetic regulation
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