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

Ali, Mourad W.; Çaçan, Ercan; Liu, Yuying; Pierce, Jennifer Young; Creasman, William T.; Murph, Mandi M.; Govindarajan, Rajgopal; Eblen, Scott T.; Greer, Susanna F.; Hooks, Shelley B.

doi:10.1371/journal.pone.0060185

Cited by 51 publications

(55 citation statements)

References 47 publications

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“…Ovarian cancer is the leading cause of mortality from gynecological cancers and the fifth most common cause of cancer mortality among females (20). An increased understanding of the molecular and genetic changes causing ovarian cancer progression is likely to produce strategies to predict and prevent the occurrence of refractory disease.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

et al. 2015

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Abstract. Ovarian cancer is the most common cause of gynecological cancer-related mortality. Serine/threonine protein phosphatase 5 (PP5, PPP5C) has been recognized to be involved in the regulation of multiple cellular signaling cascades that control diverse cellular processes, including cell growth, differentiation, proliferation, motility and apoptosis. In this study, to evaluate the functional role of PP5 in ovarian cancer cells, lentivirus-mediated RNA interference (RNAi) was applied to silence PPP5C in the human ovarian cancer cell line CAOV-3. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell colony forming ability was measured by colony formation. Cell cycle progression was determined by propidium iodide staining and flow cytometry. The results demonstrated that lentivirus-mediated RNAi specifically suppressed the expression of PPP5C at the mRNA and protein levels in CAOV-3 cells. Further investigations revealed that PP5 knockdown significantly inhibited the proliferation and colony formation of CAOV-3 cells. Moreover, the cell cycle of CAOV-3 cells was arrested at the G0/G1 phase following PP5 knockdown. This study highlights the crucial role of PP5 in promoting ovarian cancer cell proliferation, and provides a foundation for further study into the clinical potential of lentiviral-mediated delivery of PP5 RNAi therapy for the treatment of ovarian cancer. IntroductionOvarian cancer is the most common invasive malignancy of the female genital tract in the USA, with an estimated 22,240 cases diagnosed annually. Approximately 14,030 females succumb every year to ovarian cancer, representing the most common cause of mortality among females with gynecological malignancies (1). Surgical resection and platinum-based combination regimens offer a modest but significant survival advantage in ovarian cancer patients with advanced or metastatic disease, although most patients eventually experience disease progression (2). These data highlight the need to identify new approaches that, along with the current treatments, may assist in bringing about a better outcome for ovarian cancer patients.Protein kinases and phosphatases work together to control cellular processes and signaling pathways (3,4). Although much more is known about protein kinases and their relevant substrates compared with protein phosphatases (5-7), the significance of studying protein phosphatase enzymes and their targets has been demonstrated for disease states attributed in part to malfunctioning protein phosphatase enzymes (8). Protein phosphatase 5 (PP5; gene name, PPP5C) is a ubiquitously expressed serine/threonine protein phosphatase related to PP1, PP2A and PP2B (9). Structural analysis has revealed that PP5 contains a C-terminal catalytic domain and three N-terminal tetratricopeptide repeats (TPRs) that are unique in the phosphoprotein phosphatase family (10). PP5 is auto-inhibited by intramolecular interactions with its TPR domain (11).PP5 has been implicated in numerous cellular processe...

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Section: Discussionmentioning

confidence: 99%

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

et al. 2015

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“…As shown in Table IV (10,11,14,16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(29)(30)(31)(32)(33)(34)(35)(36)38,39,(41)(42)(43)(44)(45)(47)(48)(49)(50)(51)(52), we observed that a considerable number of DNA methylated genes, including MLH1, FBXO32, PROM1, RASSF1, PTEN, SFRP, TUBB3, L1TD1 and CLDN4, were associated with the invasion of ovarian cancer. Each gene was hypermethylated, resulting in the silencing of gene expression in ovarian cancer and drug-resistant tissue or cells and ultimately regulating tumour invasion.…”

Section: Correlation Analysis Of Ovarian Cancer Drug Resistance-relatmentioning

confidence: 54%

“…Among the 26 methylated genes, the methylation of ABCG2, Sulf-1, FANCF, CLDN4, TGFBI (63) and RGS10 (34) has been reported not to be associated with the prognosis of ovarian cancer. However, the methylation or abnormal expression of the remaining 20 genes are all statistically relevant to ovarian cancer prognosis.…”

Section: Correlation Analysis Of Ovarian Cancer Drug Resistance-relatmentioning

confidence: 99%

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

et al. 2016

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Abstract.The main obstacle to the successful treatment of ovarian cancer is the development of drug resistance to combined chemotherapy. Among all the factors associated with drug resistance, DNA methylation apparently plays a critical role. In this study, we performed an integrative analysis of the 26 DNA-methylated genes associated with drug resistance in ovarian cancer, and the genes were further evaluated by comprehensive bioinformatics analysis including gene/protein interaction, biological process enrichment and annotation. The results from the protein interaction analyses revealed that at least 20 of these 26 methylated genes are present in the protein interaction network, indicating that they interact with each other, have a correlation in function, and may participate as a whole in the regulation of ovarian cancer drug resistance. There is a direct interaction between the phosphatase and tensin homolog (PTEN) gene and at least half of the other genes, indicating that PTEN may possess core regulatory functions among these genes. Biological process enrichment and annotation demonstrated that most of these methylated genes were significantly associated with apoptosis, which is possibly an essential way for these genes to be involved in the regulation of multidrug resistance in ovarian cancer. In addition, a comprehensive analysis of clinical factors revealed that the methylation level of genes that are associated with the regulation of drug resistance in ovarian cancer was significantly correlated with the prognosis of ovarian cancer. Overall, this study preliminarily explains the potential correlation between the genes with DNA methylation and drug resistance in ovarian cancer. This finding has significance for our understanding of the regulation of resistant ovarian cancer by methylated genes, the treatment of ovarian cancer, and improvement of the prognosis of ovarian cancer. IntroductionOvarian cancer is a malignant tumour posing a serious threat to women's health. As the main type of ovarian cancer, ovarian epithelial carcinoma accounts for 85-90% of all ovarian cancers. The mortality rate of ovarian epithelial carcinoma ranks first among all female reproductive tract malignancies. Approximately 70% of ovarian cancer patients are in the late stage when diagnosed. Most of these tumours easily develop drug resistance in the course of post-surgery chemotherapy; therefore, the therapeutic effect is greatly reduced, leading to a survival rate of just 30% for ovarian cancer (1). Therefore, multidrug resistance is the main cause of ovarian cancer chemotherapy failure. Studies have demonstrated that multidrug resistance is the result of multiple genes or proteins and a multistep process, or cross-reactivity of multiple factors. Multidrug resistance involves several different regulatory mechanisms, and epigenetic regulation is one of the significant regulatory mechanisms in the development of ovarian cancer multidrug resistance (2). Epigenetic modification is a heritable change in gene expression without a DNA...

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“…Previous studies have demonstrated that RGS10 gene transcription was suppressed due to epigenetic regulation by DNA methyltransferase-mediated hypermethylation in the gene promoter and the histone deacetylase 1-mediated reduction of histone acetylation in cancer cells. 31,32 In failing human hearts, the GpC island in RGS10 promoter is hypomethylated compared with normal hearts 33 ; in this case, the low expression of RGS10 in failing heart was less likely to be attributed to DNA methylation. However, we acknowledge that the association between histone deacetylase 1 and the RGS10 gene may be a potential mechanism for RGS10 reduction in hypertrophic hearts because class I HDACs (including histone deacetylase 1) are prominently prohypertrophic factors that induce cardiac hypertrophic response to AB or Ang II.…”

Section: Discussionmentioning

confidence: 93%

Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

Miao

Xing

et al. 2016

Hypertension

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Regulator of G-protein signaling 10 (RGS10) is an important member of the RGS family and produces biological effects in multiple organs. We used a genetic approach to study the role of RGS10 in the regulation of pathological cardiac hypertrophy and found that RGS10 can negatively influence pressure overload–induced cardiac remodeling. RGS10 expression was markedly decreased in failing human hearts and hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in RGS10-knockout mice was exacerbated, whereas the heart of transgenic mice with cardiac-specific RGS10 overexpression exhibited an alleviated response to pressure overload. Consistently, RGS10 also inhibited an angiotensin II–induced hypertrophic response in isolated cardiomyocytes. Mechanistically, cardiac remodeling improvement elicited by RGS10 was associated with the abrogation of mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated protein kinase 1/2 signaling. Furthermore, the inhibition of mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 transduction abolished RGS10 deletion-induced hypertrophic aggravation. These findings place RGS10 and its downstream signaling mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 as crucial regulators of pathological cardiac hypertrophy after pressure overload and identify this pathway as a potential therapeutic target to attenuate the pressure overload–driven cardiac remodeling.

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

Cited by 51 publications

References 47 publications

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

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