Title: Aberrant Activation of β-Catenin Signaling Drives Glioma Tumorigenesis via USP1-Mediated Stabilization of EZH2.
Authors: Ma, Li; Lin, Kangyu; Chang, Guoqiang; Chen, Yiwen; Yue, Chen; Guo, Qing; Zhang, Sicong; Jia, Zhiliang; Huang, Tony T; Zhou, Aidong; Huang, Suyun
Published In Cancer Res, (2019 01 01)
Abstract: Aberrant activation of β-catenin signaling is a critical driver for tumorigenesis, but the mechanism underlying this activation is not completely understood. In this study, we demonstrate a critical role of β-catenin signaling in stabilization of enhancer of zeste homolog 2 (EZH2) and control of EZH2-mediated gene repression in oncogenesis. β-Catenin/TCF4 activated the transcription of the deubiquitinase USP1, which then interacted with and deubiquitinated EZH2 directly. USP1-mediated stabilization of EZH2 promoted its recruitment to the promoters of CDKN1B, RUNX3, and HOXA5, resulting in enhanced enrichment of histone H3K27me3 and repression of target gene expression. In human glioma specimens, expression levels of nuclear β-catenin, USP1, and EZH2 correlated with one another. Depletion of β-catenin/USP1/EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a β-catenin-USP1-EZH2 axis orchestrates the interplay between dysregulated β-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. SIGNIFICANCE: These findings identify the β-catenin-USP1-EZH2 signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.
PubMed ID: 30425057
MeSH Terms: Animals; Carcinogenesis/genetics; Carcinogenesis/metabolism; Carcinogenesis/pathology*; Cell Proliferation; Enhancer of Zeste Homolog 2 Protein/chemistry*; Enhancer of Zeste Homolog 2 Protein/genetics; Enhancer of Zeste Homolog 2 Protein/metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic*; Glioma/genetics; Glioma/metabolism; Glioma/pathology*; Humans; Mice; Mice, Nude; Prognosis; Protein Stability; Survival Rate; Tumor Cells, Cultured; Ubiquitin-Specific Proteases/genetics; Ubiquitin-Specific Proteases/metabolism*; Xenograft Model Antitumor Assays; beta Catenin/genetics; beta Catenin/metabolism*