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Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.

ABSTRACT: Inactivation of the tumor suppressor Ras-association domain family 1 isoform A (RASSF1A) due to epigenetic silencing occurs in a variety of human cancers, and still largely unknown are the regulators and mechanisms underlying RASSF1A gene promoter methylation. Herein, we report that this methylation is regulated by p53 and death-associated protein 6 (DAXX) in acute lymphoblastic leukemia (ALL). We found that p53 bound to the RASSF1A promoter, recruiting DAXX as well as DNA methyltransferase 1 (DNMT1) for DNA methylation, which subsequently resulted in inactivation of RASSF1A in wild-type p53 ALL cells. Although the presence of p53 was required for the recruitment of DAXX and DNMT1 to the RASSF1A promoter, fluctuation in p53 protein levels did not affect the rates of RASSF1A methylation. Conversely, methylation of RASSF1A promoter was critically controlled by DAXX, as the enforced overexpression of DAXX led to enhanced RASSF1A promoter methylation, whereas inhibition of DAXX reduced RASSF1A methylation. Interestingly, we found that the p53/DAXX-mediated RASSF1A methylation regulated murine double minute 2 (MDM2) protein stability in ALL. Our results reveal a novel function for p53 in the methylation of RASSF1A promoter by its interaction with DAXX. Discovery of this mechanism provides new insight into the interactions among the tumor-related factors p53, RASSF1A, DAXX, and MDM2 in cancer pathogenesis.

SUBMITTER: Zhang H

PROVIDER: S-EPMC3528318 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.

Zhang Hailong H He Jing J Li Jiansha J Tian Dan D Gu Lubing L Zhou Muxiang M

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20121004 1

Inactivation of the tumor suppressor Ras-association domain family 1 isoform A (RASSF1A) due to epigenetic silencing occurs in a variety of human cancers, and still largely unknown are the regulators and mechanisms underlying RASSF1A gene promoter methylation. Herein, we report that this methylation is regulated by p53 and death-associated protein 6 (DAXX) in acute lymphoblastic leukemia (ALL). We found that p53 bound to the RASSF1A promoter, recruiting DAXX as well as DNA methyltransferase 1 (D ...[more]

PMID: 23038753

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Project description:BackgroundThe function of the tumor suppressor gene RASSF1A in cancer cells has been detailed in many studies. However, due to the methylation of its promoter, the expression of RASSF1A is missing in most cancers. In the literature, we found that the conclusion regarding the relationship between RASSF1A gene promoter methylation and the susceptibility and prognosis of melanoma was not unified. This study adopts the use of a meta-analysis and bioinformatics to explore the relationship between RASSF1A gene promoter methylation and the susceptibility and prognosis of melanoma.MethodsData on melanoma susceptibility were downloaded from the PubMed, Cochrane Library, Web of Science and Google Scholar databases, which were analyzed via a meta-analysis. The effect sizes were estimated by measuring an odds ratio (OR) with a 95% confidence interval (CI). We also used a chi-squared-based Q test to examine the between-study heterogeneity, and used funnel plots to evaluate publication bias. The data on melanoma prognosis, which were analyzed by bioinformatics methods, were downloaded from The Cancer Genome Atlas (TCGA) project. The effect sizes were estimated by measuring the hazard ratios (HRs) with a 95% confidence interval (CI).ResultsOur meta-analysis included 10 articles. We found that RASSF1A gene promoter methylation was closely related to melanoma susceptibility (OR = 12.67, 95% CI: 6.16 ∼ 26.05, z = 6.90, P<0.0001 according to a fixed effects model and OR = 9.25, 95% CI: 4.37 ∼ 19.54, z = 5.82, P<0.0001 according to a random effects model). The results of the meta-analysis did not reveal any heterogeneity (tau2 = 0.00; H = 1 [1; 1.55]; I2 = 0% [0%; 58.6%], P = 0.5158) or publication bias (t = 0.87, P = 0.4073 by Egger's test; Z = 0.45, P = 0.6547 by Begg's test); therefore, we believe that the results of our meta-analysis were more reliable. To explore the relationship between RASSF1A gene methylation, the prognosis of melanoma and the clinical features of this cancer type, we used the melanoma DNA methylation data and clinical data from TCGA project. We found that RASSF1A gene promoter methylation and melanoma prognosis did not demonstrate any relationship (HR was 0.94 (95% CI = [0.69; 1.27], P = 0.694) with disease-free survival and 0.74 (95% CI = [0.53; 1.05], P = 0.106) for overall survival), and no significant difference was observed between RASSF1A gene promoter methylation and the clinical-pathological features of melanoma.ConclusionsIn conclusion, the meta-analysis of the data in these articles provides strong evidence that the methylation status of the RASSF1A gene promoter was strongly related to melanoma susceptibility. Our bioinformatics analysis revealed no significant difference between RASSF1A gene promoter methylation and the prognosis and clinical-pathological features of melanoma.

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Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.

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Methylation of RASSF1A gene promoter is regulated by p53 and DAXX.

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