Aberrant activation of b-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2

Li Ma, Kangyu Lin, Guoqiang Chang, Yiwen Chen, Chen Yue, Qing Guo, Sicong Zhang, Zhiliang Jia, Tony T. Huang, Ai-Dong Zhou, Suyun Huang

Research output: Contribution to journalArticle

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Abstract

Aberrant activation of b-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 b-catenin signaling in stabilization of enhancer of zeste homolog 2 (EZH2) and control of EZH2-mediated gene repression in oncogenesis. b-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 b-catenin, USP1, and EZH2 correlated with one another. Depletion of b-catenin/USP1/ EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a b-catenin–USP1-EZH2 axis orchestrates the interplay between dysregulated b-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. Significance: These findings identify the b-catenin-USP1-EZH2 signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.

Original languageEnglish (US)
Pages (from-to)72-85
Number of pages14
JournalCancer Research
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2019

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Catenins
Glioma
Carcinogenesis
Enhancer of Zeste Homolog 2 Protein
Gene Silencing
Glioblastoma
Epigenomics
Histones
Cell Proliferation
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aberrant activation of b-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. / Ma, Li; Lin, Kangyu; Chang, Guoqiang; Chen, Yiwen; Yue, Chen; Guo, Qing; Zhang, Sicong; Jia, Zhiliang; Huang, Tony T.; Zhou, Ai-Dong; Huang, Suyun.

In: Cancer Research, Vol. 79, No. 1, 01.01.2019, p. 72-85.

Research output: Contribution to journalArticle

Ma, L, Lin, K, Chang, G, Chen, Y, Yue, C, Guo, Q, Zhang, S, Jia, Z, Huang, TT, Zhou, A-D & Huang, S 2019, 'Aberrant activation of b-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2', Cancer Research, vol. 79, no. 1, pp. 72-85. https://doi.org/10.1158/0008-5472.CAN-18-1304
Ma, Li ; Lin, Kangyu ; Chang, Guoqiang ; Chen, Yiwen ; Yue, Chen ; Guo, Qing ; Zhang, Sicong ; Jia, Zhiliang ; Huang, Tony T. ; Zhou, Ai-Dong ; Huang, Suyun. / Aberrant activation of b-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. In: Cancer Research. 2019 ; Vol. 79, No. 1. pp. 72-85.
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