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Epigenetic regulation of regulators of G‐protein signaling RGS10 and RGS17 expression in chemoresistant ovarian cancer cells
Author(s) -
Ali Mourad Wagdy,
Callihan Phillip,
Altman Molly,
Murph Mandi,
Hooks Shelley
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.838.2
Subject(s) - dna methylation , biology , cpg site , epigenetics , ovarian cancer , cancer research , rgs2 , cancer , methylation , signal transduction , gene , gene expression , microbiology and biotechnology , g protein , genetics , gtpase activating protein
The development of chemoresistance represents a critical therapeutic challenge in epithelial ovarian carcinoma. Receptor‐stimulated survival pathways are amplified in chemoresistant cells. RGS proteins suppress GPCR stimulated signaling. We have recently reported RGS2, 10, and 17 are downregulated in models of acquired chemoresistance in ovarian cancer. Further, RGS transcript expression is decreased following short term exposure to chemotherapeutic drugs. This suggests a model in which RGS expression is reduced following exposure to chemotherapeutic drugs, thus indirectly amplifying GPCR mediated survival signaling. The current study investigates mechanisms for suppressed RGS transcript expression in chemoresistant ovarian cancer cells. Our analysis shows that RGS2, 10, and 17 gene promoters have high GC content, suggesting that DNA methylation could negatively regulate expression of these RGS transcripts. Treatment with 5‐azacytidine, an inhibitor of DNA methyltransferase increased expression of RGS2, 10 and 17. We measured DNA methylation across the promoter regions of these RGS genes, and compared frequency of methylation at specific CpG sites in normal and chemoresistant cell lines and following acute exposure to chemotherapy. This research has been funded by NIH, Elsa Pardee Foundation and Georgia Cancer Coalition.