Abstract 2479: A survey of molecular factors of DNA methylation and demethylation in a broad range of cancer cell lines

Abstract

Abstract DNA methylation has a powerful influence on cellular processes. It plays important roles in cancer initiation and progression. Cancer cells exhibit frequent epigenomic alterations that affect expression of genes involved in apoptosis, cell proliferation, and DNA repair. We used expression information of known methylating and demethylating genes in cancer cell lines to analyze their association with methylation levels of individual probes and median epigenome-wide methylation levels. We utilized RNA-seq gene expression measures and Illumina Infinium HumanMethylation450 BeadChip DNA methylation data of 645 cancer cell lines from 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer resources. We analyzed 73 genes, products of which are involved in methylation and demethylation processes, and examined correlations between expression levels of these genes and methylation status of individual probes and epigenome-wide. In a combined analysis across all cancer types, we observed statistically significant correlations between expression of global DNA methyltransferase genes, DNMT1, DNMT3A, and DNMT3B, and probe methylation levels in 566, 909, and 230 genes, respectively. In particular, DNMT3A expression was associated with methylation status of growth factor and receptor genes FGF1, FGFR4, and EGFR. Expression of hydroxymethylating genes TET1, TET2, and TET3 was correlated with methylation status of probes in 363, 1, and 1055 genes, respectively, including associations of TET3 expression with methylation of probes in the FGF1, KIT, FHIT, IGF1R, IGF2BP2, and PARP3 genes, which may affect growth, proliferation, and DNA repair of tumor cells. APOBEC1, CBX2, UHRF1 and ZBTB38, products of which are involved in various molecular steps of DNA methylation or demethylation, had the largest numbers of associations in different cancer types. For example, in chronic lymphocytic leukemia cell lines we observed a strong negative correlation between ZBTB38 expression, the product of which binds methylated DNA, and methylation levels of probes in 204 genes. We also found a strong correlation between UHRF1 gene expression and methylation levels of probes in 150 genes in chronic lymphocytic leukemia cell lines, in agreement with reported roles of the product of this gene in binding DNA methyltransferases and affecting DNMT1 methylation activity. These results provide a better understanding of molecular mechanisms of epigenetic dysregulation in cancer cells and may provide strategies for future analysis of molecular targets of drug response that may be affected via epigenetic processes. Citation Format: Suleyman Vural, Julia Krushkal. A survey of molecular factors of DNA methylation and demethylation in a broad range of cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2479.