title: DNMT1 as a molecular target in a multimodality-resistant phenotype in tumor cells.
abstract: 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 H(2)O(2), 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 H(2)O(2), 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(2)O(2), 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 H(2)O(2), 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(2)O(2)) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Mishra
authors.forename: Kheem S
authors.initials: KS
authors.lastname: Bisht
authors.forename: Lunching
authors.initials: L
authors.lastname: Sun
authors.forename: Kristi
authors.initials: K
authors.lastname: Muldoon-Jacobs
authors.forename: Rania
authors.initials: R
authors.lastname: Awwad
authors.forename: Aradhana
authors.initials: A
authors.lastname: Kaushal
authors.forename: Phuongmai
authors.initials: P
authors.lastname: Nguyen
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Pennington
authors.forename: Stephanie
authors.initials: S
authors.lastname: Markovina
authors.forename: C Matthew
authors.initials: CM
authors.lastname: Bradbury
authors.forename: David
authors.initials: D
authors.lastname: Gius
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D001374:Azacitidine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006861:Hydrogen Peroxide; D016760:Proto-Oncogene Proteins c-fos; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat