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Cancer Sci. 2018 Jun;109(6):1876-1888. doi: 10.1111/cas.13612. Epub 2018 May 23.

Plakoglobin restores tumor suppressor activity of p53R175H mutant by sequestering the oncogenic potential of β-catenin.

Author information

1
Department of Oncology, University of Alberta, Edmonton, Canada.

Abstract

Tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins have not only lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H ) with well-documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signaling protein and a paralog of β-catenin. Unlike β-catenin that has oncogenic function through its role in the Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor. We have shown that plakoglobin interacted with wild type and a number of p53 mutants in various carcinoma cell lines. Plakoglobin and mutant p53 interacted with the promoter and regulated the expression of several p53 target genes. Furthermore, plakoglobin interactions with p53 mutants restored their tumor suppressor/metastasis activities in vitro. GOF p53 mutants induce accumulation and oncogenic activation of β-catenin. Previously, we showed that one mechanism by which plakoglobin may suppress tumorigenesis is by sequestering β-catenin's oncogenic activity. Here, we examined the effects of p53R175H expression on β-catenin accumulation and transcriptional activation and their modifications by plakoglobin coexpression. We showed that p53R175H expression in plakoglobin null cells increased total and nuclear levels of β-catenin and its transcriptional activity. Coexpression of plakoglobin in these cells promoted β-catenin's proteasomal degradation, and decreased its nuclear levels and transactivation. Wnt/β-catenin targets, c-MYC and S100A4 were upregulated in p53R175H cells and were downregulated when plakoglobin was coexpressed. Plakoglobin-p53R175H cells also showed significant reduction in their migration and invasion in vitro.

KEYWORDS:

invasion; p53; p53R175H; plakoglobin; β-catenin

PMID:
29660231
PMCID:
PMC5989865
DOI:
10.1111/cas.13612
[Indexed for MEDLINE]
Free PMC Article

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