DNMT Inhibitors Increase Methylation in the Cancer Genome

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Giri , A K & Aittokallio , T 2019 , ' DNMT Inhibitors Increase Methylation in the Cancer Genome ' , Frontiers in Pharmacology , vol. 10 , 385 . https://doi.org/10.3389/fphar.2019.00385

Title: DNMT Inhibitors Increase Methylation in the Cancer Genome
Author: Giri, Anil K.; Aittokallio, Tero
Contributor organization: Helsinki Institute for Information Technology
Tero Aittokallio / Principal Investigator
Institute for Molecular Medicine Finland
Department of Computer Science
Date: 2019-04-24
Language: eng
Number of pages: 11
Belongs to series: Frontiers in Pharmacology
ISSN: 1663-9812
DOI: https://doi.org/10.3389/fphar.2019.00385
URI: http://hdl.handle.net/10138/303573
Abstract: DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (vertical bar r vertical bar >= 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.
Subject: DNA methyltransferase inhibitors
anticancer treatment
olfactory receptor pathway
alternative splicing
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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