title: Increased DNA methyltransferase activity and DNA methylation following Epidermal Growth Factor stimulation in ovarian cancer cells.
abstract: Ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation. In ovarian cancer, ascites fluid contains numerous Epidermal-Growth-Factor-Receptor (EGFR) activators, which could result in a tumor microenvironment of constant EGFR activation. Signaling pathways downstream of EGFR, such as Ras, regulate DNA methylation. We hypothesized that chronic EGFR activation could alter DNA methylation. We found that EGFR activation increased DNA methyltransferase (DNMT) activity acutely, as well as after long-term EGF treatment or expression of a mutationally activated EGFR. Furthermore, this increase in DNMT activity was dependent on EGFR catalytic activity and resulted in increased global DNA methylation. Additionally, treatment with the DNMT inhibitor/hypomethylating agent 5-Aza-2'-deoxycytidine (AZA) inhibited the EGF induced increase of both DNMT activity and global methylation. These data support a role for EGFR in the process of accumulated DNA methylation during ovarian cancer progression and suggest that epigenetic therapy may be beneficial for the treatment of ovarian cancer.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA. sruiz@salud.unm.edu
authors.forename: Sabrina L
authors.initials: SL
authors.lastname: Samudio-Ruiz
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology
chemical_list: D004815:Epidermal Growth Factor; D015254:DNA Modification Methylases; D066246:ErbB Receptors