DNMT1 as a molecular target in a multimodality-resistant phenotype in tumor cells

Mark V. Mishra, Kheem S. Bisht, Lunching Sun, Kristi Muldoon-Jacobs, Rania Awwad, Aradhana Kaushal, Phuongmai Nguyen, Lei Huang, J. Daniel Pennington, Stephanie Markovina, C. Matthew Bradbury, David Gius

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


We have previously shown that hydrogen peroxide-resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H2O2, etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H2O2, etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos-overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos-overexpressing cells were exposed to 5-aza-2′- deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H 2O2, etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1-/-) or DNMT3B (DNMT3B-/-) were shown to be more sensitive to the cytotoxicity of H2O2, etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H 2O2) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy.

Original languageEnglish
Pages (from-to)243-249
Number of pages7
JournalMolecular Cancer Research
Issue number2
StatePublished - Feb 1 2008


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