Transcriptional Suppression, DNA Methylation, and Histone Deacetylation of the Regulator of G-Protein Signaling 10 (RGS10) Gene in Ovarian Cancer Cells

Ali, Mourad W.; Cacan, Ercan; Liu, Yuying; Pierce, Jennifer Young; Creasman, William T.; Murph, Mandi M.; Govindarajan, Rajgopal; Eblen, Scott T.; Greer, Susanna F.; Hooks, Shelley B.
March 2013
PLoS ONE;Mar2013, Vol. 8 Issue 3, p1
Academic Journal
RGS10 regulates ovarian cancer cell growth and survival, and RGS10 expression is suppressed in cell models of ovarian cancer chemoresistance. However, the mechanisms governing RGS10 expression in ovarian cancer are poorly understood. Here we report RGS10 suppression in primary ovarian cancer and CAOV-3 ovarian cancer cells compared to immortalized ovarian surface epithelial (IOSE) cells, and in A2780-AD chemoresistant cells compared to parental A2780 cells. RGS10-1 and RGS10-2 transcripts are expressed in ovarian cancer cells, but only RGS10-1 is suppressed in A2780-AD and CAOV-3 cells, and the RGS10-1 promoter is uniquely enriched in CpG dinucleotides. Pharmacological inhibition of DNA methyl-transferases (DNMTs) increased RGS10 expression, suggesting potential regulation by DNA methylation. Bisulfite sequencing analysis identified a region of the RGS10-1 promoter with significantly enhanced DNA methylation in chemoresistant A2780-AD cells relative to parental A2780 cells. DNA methylation in CAOV-3 and IOSE cells was similar to A2780 cells. More marked differences were observed in histone acetylation of the RGS10-1 promoter. Acetylated histone H3 associated with the RGS10-1 promoter was significantly lower in A2780-AD cells compared to parental cells, with a corresponding increase in histone deacetylase (HDAC) enzyme association. Similarly, acetylated histone levels at the RGS10-1 promoter were markedly lower in CAOV-3 cells compared to IOSE cells, and HDAC1 binding was doubled in CAOV-3 cells. Finally, we show that pharmacological inhibition of DNMT or HDAC enzymes in chemoresistant A2780-AD cells increases RGS10 expression and enhances cisplatin toxicity. These data suggest that histone de-acetylation and DNA methylation correlate with RGS10 suppression and chemoresistance in ovarian cancer. Markers for loss of RGS10 expression may identify cancer cells with unique response to therapeutics.


Related Articles

  • Outline of Therapeutic Interventions With Muscarinic Receptor- Mediated Transmission. JAKUBÍK, J.; ŠANTRŮČKOVÁ, E.; RANDÁKOVÁ, A.; JANÍČKOVÁ, H.; ZIMČÍK, P.; RUDAJEV, V.; MICHAL, P.; EL-FAKAHANY, E. E.; DOLEŽAL, V. // Physiological Research;2014 Supplement 1, Vol. 63 Issue S1, pS177 

    Muscarinc receptor-mediated signaling takes part in many physiological functions ranging from complex higher nervous activity to vegetative responses. Specificity of action of the natural muscarinic agonist acetylcholine is effected by action on five muscarinic receptor subtypes with particular...

  • Classification of G proteins and prediction of GPCRs-G proteins coupling specificity using continuous wavelet transform and information theory. Li, Zhanchao; Zhou, Xuan; Dai, Zong; Zou, Xiaoyong // Amino Acids;Aug2012, Vol. 43 Issue 2, p793 

    The coupling between G protein-coupled receptors (GPCRs) and guanine nucleotide-binding proteins (G proteins) regulates various signal transductions from extracellular space into the cell. However, the coupling mechanism between GPCRs and G proteins is still unknown, and experimental...

  • Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Shukla, Arun K.; Manglik, Aashish; Kruse, Andrew C.; Xiao, Kunhong; Reis, Rosana I.; Tseng, Wei-Chou; Staus, Dean P.; Hilger, Daniel; Uysal, Serdar; Huang, Li-Yin; Paduch, Marcin; Tripathi-Shukla, Prachi; Koide, Akiko; Koide, Shohei; Weis, William I.; Kossiakoff, Anthony A.; Kobilka, Brian K.; Lefkowitz, Robert J. // Nature;5/2/2013, Vol. 497 Issue 7447, p137 

    The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other...

  • Adenosine Receptors: Expression, Function and Regulation. Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram // International Journal of Molecular Sciences;Feb2014, Vol. 15 Issue 2, p2024 

    Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiological actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and...

  • The Downstream Regulation of Chemokine Receptor Signalling: Implications for Atherosclerosis. Patel, Jyoti; Channon, Keith M.; McNeill, Eileen // Mediators of Inflammation;2013, Vol. 2013, p1 

    Heterotrimeric G-protein-coupled receptors (GPCRs) are key mediators of intracellular signalling, control numerous physiological processes, and are one of the largest class of proteins to be pharmacologically targeted. Chemokine-induced macrophage recruitment into the vascular wall is an early...

  • Mechanisms of the 14-3-3 Protein Function: Regulation of Protein Function Through Conformational Modulation. OBSILOVA, V.; KOPECKA, M.; KOSEK, D.; KACIROVA, M.; KYLAROVA, S.; REZABKOVA, L.; OBSIL, T. // Physiological Research;2014 Supplement 1, Vol. 63 Issue S1, pS155 

    Many aspects of protein function regulation require specific protein-protein interactions to carry out the exact biochemical and cellular functions. The highly conserved members of the 14-3-3 protein family mediate such interactions and through binding to hundreds of other proteins provide...

  • Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs). Kai Yang; Jackson, Michael F.; MacDonald, John F. // International Journal of Molecular Sciences;Feb2014, Vol. 15 Issue 2, p3003 

    G Protein Coupled Receptors (GPCRs) are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs), which belong to the ionotropic...

  • Identification of a Novel Protein-Protein Interaction Motif Mediating Interaction of GPCR-Associated Sorting Proteins with G Protein-Coupled Receptors. Bornert, Olivier; Møller, Thor C.; Boeuf, Julien; Candusso, Marie-Pierre; Wagner, Renaud; Martinez, Karen L.; Simonin, Frederic // PLoS ONE;Feb2013, Vol. 8 Issue 2, p1 

    GPCR desensitization and down-regulation are considered key molecular events underlying the development of tolerance in vivo. Among the many regulatory proteins that are involved in these complex processes, GASP-1 have been shown to participate to the sorting of several receptors toward the...

  • Regulation of Constitutive GPR3 Signaling and Surface Localization by GRK2 and β-arrestin-2 Overexpression in HEK293 Cells. Lowther, Katie M.; Uliasz, Tracy F.; Götz, Konrad R.; Nikolaev, Viacheslav O.; Mehlmann, Lisa M. // PLoS ONE;Jun2013, Vol. 8 Issue 6, p1 

    G protein-coupled receptor 3 (GPR3) is a constitutively active receptor that maintains high 3′-5′-cyclic adenosine monophosphate (cAMP) levels required for meiotic arrest in oocytes and CNS function. Ligand-activated G protein-coupled receptors (GPCRs) signal at the cell surface and...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics