Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance.
RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.
Division of Cellular Biology and Immunology, Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
Ercan
E
Cacan
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
Mourad W
MW
Ali
Division of Cellular Biology and Immunology, Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
Nathaniel H
NH
Boyd
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
Shelley B
SB
Hooks
Division of Cellular Biology and Immunology, Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
Susanna F
SF
Greer
D047369:Chromatin Immunoprecipitation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction
D017931:DNA Primers; D020710:RGS Proteins; C101113:RGS10 protein, human; D034741:RNA, Small Interfering; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1