The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically

Zhibin Yu,Changhong Liu,Yan Zhang,Jianbo Feng,Zeyou Wang,Lan Xiao,Wei Wang,Shuai Chen,Zhiyong Deng,Qing Liu,Minghua Wu

doi:10.1038/s41388-020-1206-7

Abstract

The homeotic protein SIX3 is a transcription factor vital for neurogenesis and has a bivalent promoter. We previously showed that SIX3 can be transcriptionally silenced by DNA hypermethylation, functions as a tumor suppressor gene, and inhibits human glioblastoma transcriptionally. Here, we show that the activation of epidermal growth factor (EGFR) induces DNA methylation of SIX3 promoter through the MAPK pathway. ERK, when activated, binds with ZNF263, consequently abrogating the ubiquitination of ZNF263 and leading to its stabilization. ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and methylation of SIX3 promoter. Activation of the EGFR-ZNF263 signaling axis in phenotypically normal astrocytes or glioblastoma cells triggers or enhances tumorigenic activities, while elevated expression of the EGFR-ZNF263 signaling components in glioblastoma tissues is associated with poor prognosis of the patients. Together, our findings demonstrate that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma.

Highlights

During tumorigenesis, cells undergo a genome-wide epigenetic reprogramming process, which contributes to massive overall DNA hypomethylation and specific hypermethylation at certain CpG promoters [1, 2]
In this study, using the results from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed the level of methylation on the CpG island of SIX3 promoter and confirmed our earlier findings that SIX3 is hypermethylated in both low-grade glioma and glioblastoma (Fig. 1a, S1A)
One argues that hypermethylation of tumor suppressor genes (TSG) results from a stochastic process, such as mutations of DNMTs or TETs, which causes extensive abnormalities in the methylome, while the cells with TSG hypermethylation are enabled with selectable growth advantages

Summary

Introduction

Cells undergo a genome-wide epigenetic reprogramming process, which contributes to massive overall DNA hypomethylation and specific hypermethylation at certain CpG promoters [1, 2]. DNA methylation controls the transcription activity of the associated gene together with histone modifications [3,4,5]. Abundant tumor suppressor genes (TSG) are reportedly silenced by DNA methylation and histone modifications in human cancer [4, 6, 7]. A CpG island methylator phenotype (G-CIMP) has been identified primarily in the secondary glioblastoma and leads to much improved survival of G-CIMP patients [12]. While H3.3K27M, IDH1 mutations are detected in a small fraction of glioblastoma patients, the mechanism by which oncogenic mutations remodel the epigenome are still poorly understood [13,14,15,16]

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Results

Conclusion