Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines

Abstract

Background Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. Results We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation. Conclusions Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

“…8 L). Among these candidate molecular targets, nine were significantly enriched in all three cohorts, and five of them (TP53BP1 [ 25 ], RIPK2 [ 26 ], EHMT2 [ 27 ], IGFBP3 [ 28 ], and HMOX1 [ 29 ]) have been reported to have cancer- and chemoresistance-promoting activities simultaneously. Particularly, although EHMT2, a member of the histone methyltransferase family, was identified in all three cohorts, the transcription level of EHMT2 was significantly higher in the fluorouracil-response group (Fig.…”

Cisplatin resistance-related multi-omics differences and the establishment of machine learning models

“…Similar to the IRF5, in our experiment, its expression is related to cisplatin sensitivity. Previous study showed that ZBTB38 can enhance the response to DNMT inhibitor therapies as a target of DNA methyltransferase inhibitor [ 36 ] as well as it can influence response of cancer cell lines to chemotherapy through involving in diverse epigenetic processes affecting DNA methylation [ 37 ]. However, The biological function of ZBTB38 remains also elusive [ 38 ].…”

Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer

“…We also identified that Cas9 -mediated loss of PALB2 , RAD51, RAD51C, RNASEH2A, XRCC1, and XRCC3 conferred olaparib sensitivity in at least 3 out of 6 cell lines. These results suggest that to some extent the effect of those genes on olaparib sensitivity can be dependent on several factors intrinsic to the cell lines such as genetic and epigenetic backgrounds [ 62 , 63 ], and clinical parameters from the original tumors where the cell lines were established (sampling site and pretreatment) [ 64 ]. Therefore, additional studies are necessary to fully elucidate those dependencies for increased PARPi sensitivity in each gene.…”