Concerted changes in transcriptional regulation of genes Involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism in the NCI60 cancer cell line panel in response to cancer drug treatment

Authors

• J Krushkal
• Y Zhao
• C Hose
• A Monks
• JH Doroshow
• R Simon

Abstract

Aberrant patterns of DNA methylation are common in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Reactions in the folate-mediated one-carbon metabolism pathway are linked to DNA methylation and to other vital cell functions. We used the Transcriptional Pharmacology Workbench, an online bioinformatics tool developed by the Biometric Research Branch of the National Cancer Institute, to examine temporal changes in gene expression among epigenetic components of DNA methylation and demethylation pathways and among members of the one-carbon metabolism pathway in response to cancer drug treatment. We analyzed gene expression changes in the NCI60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Treatment with each agent led to concerted changes in expression of multiple pathway components across the cell lines. We also observed changes in expression of important DNA methylation target genes, including reactivation of tumor suppressor genes and changes in expression of genes involved in DNA replication, damage response, and repair, cell growth arrest, and apoptosis. These concerted changes suggest common underlying biological response mechanisms among different tumor types. Concerted changes in expression of epigenetic factors and of components of the one-carbon metabolism pathway likely affect vital cellular processes and may contribute to cytotoxic and apoptotic action of the cancer drugs. The concerted molecular response among multiple cell lines was observed in a time-dependent manner, which may provide suggestions for the timing of administration of these antitumor agents in drug combination therapy treatment. Funded by NCI Contract HHSN261200800001E.

Scientific Focus Area: Computational Biology

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