The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically

Oncogene. 2020 Apr;39(15):3163-3178. doi: 10.1038/s41388-020-1206-7.

Zhibin Yu ^# ¹ ² ³, Jianbo Feng ^# ¹ ², Wei Wang ⁴, Zhiyong Deng ¹, Yan Zhang ¹ ², Lan Xiao ², Zeyou Wang ⁵, Changhong Liu ¹ ², Qing Liu ⁶, Shuai Chen ⁷, Minghua Wu ⁸ ⁹

Affiliations

1 Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China.
2 Cancer Research Institute, School of Basic Medical Science, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, 410078, Hunan, China.
3 Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
4 Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, 272000, Shandong, China.
5 Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
6 Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
7 Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China. [email protected].
8 Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China. [email protected].
9 Cancer Research Institute, School of Basic Medical Science, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, 410078, Hunan, China. [email protected].
# Contributed equally.

PMID: 32051553 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.

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