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DNA Damage and Cellular Stress Responses

DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells

Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: David Gius, Radiation Oncology Branch, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-496-5457. E-mail: giusd{at}mail.nih.gov

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 H₂O₂, 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 (H₂O₂) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy. (Mol Cancer Res 2008;6(2):243–9)