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DNA Methylation Activates TP73 Expression in Hepatocellular Carcinoma and Gastrointestinal Cancer.

ABSTRACT: The complexity of TP73 expression and its functionality, as well as the role of TP73 in tumorigenesis, unlike its cousin TP53, which is an established tumor suppressor, have remained elusive to date. In this study, we isolated two stem cell lines (HepCY & HepCO) from normal young and old human liver tissues. We determined TP73 expression in HepCY and HepCO, hepatocellular cancer (HCC) cell lines (HepG2, SNU398, SNU449 and SNU475), gastrointestinal cancer (GI) cell lines (Caco2 and HCT116) and normal skin fibroblasts cell line (HS27). Immunohistochemical analyses of TP73 expression was also performed in non-cancerous and adjacent cancerous liver tissues of HCC patients. The results show that TP73 expression is exclusive to the cancer cell lines and not the adjacent normal liver tissues. Moreover, methylation-specific PCR and bisulfite sequencing studies revealed that TP73 promoter is activated only in cancer cell lines by DNA methylation. Furthermore, ChIP assay results demonstrated that a chromosomal networking protein (CTCF) and tumor protein p53 (TP53) bind to TP73 promoter and regulate TP73 expression. Our observations demonstrate that a positive correlation in tumorigenesis exists between TP73 expression and DNA methylation in promoter regions of TP73. These findings may prove significant for the development of future diagnostic and therapeutic applications.

SUBMITTER: Yao Z

PROVIDER: S-EPMC6920427 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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DNA Methylation Activates TP73 Expression in Hepatocellular Carcinoma and Gastrointestinal Cancer.

Yao Zhixing Z Di Poto Cristina C Mavodza Grace G Oliver Everett E Ressom Habtom W HW Sherif Zaki A ZA

Scientific reports 20191218 1

The complexity of TP73 expression and its functionality, as well as the role of TP73 in tumorigenesis, unlike its cousin TP53, which is an established tumor suppressor, have remained elusive to date. In this study, we isolated two stem cell lines (HepCY & HepCO) from normal young and old human liver tissues. We determined TP73 expression in HepCY and HepCO, hepatocellular cancer (HCC) cell lines (HepG2, SNU398, SNU449 and SNU475), gastrointestinal cancer (GI) cell lines (Caco2 and HCT116) and no ...[more]

PMID: 31852961

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Project description:BackgroundHepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients.MethodsA set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines.ResultsDNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005).ConclusionsOur data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model.

Dataset Information

DNA Methylation Activates TP73 Expression in Hepatocellular Carcinoma and Gastrointestinal Cancer.

Publications

DNA Methylation Activates TP73 Expression in Hepatocellular Carcinoma and Gastrointestinal Cancer.

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