Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China.
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.
Oncogene. 2020 Apr;39(15):3163-3178. doi: 10.1038/s41388-020-1206-7. Epub 2020 Feb 13.
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.
同源盒蛋白 SIX3 是一种对神经发生至关重要的转录因子，具有双重启动子。我们之前曾表明，SIX3 可以通过 DNA 超甲基化被转录沉默，作为一种肿瘤抑制基因，抑制人胶质母细胞瘤转录。在这里，我们表明表皮生长因子 (EGFR) 的激活通过 MAPK 途径诱导 SIX3 启动子的 DNA 甲基化。ERK 被激活后，与 ZNF263 结合，从而消除 ZNF263 的泛素化，使其稳定。ZNF263 与 SIX3 的核心启动子区域结合，并募集 KAP1/HATS/DNMT 核心抑制复合物，通过 H3K27me3 和 SIX3 启动子甲基化诱导 SIX3 的转录沉默。表型正常的星形胶质细胞或胶质母细胞瘤细胞中 EGFR-ZNF263 信号轴的激活触发或增强致瘤活性，而胶质母细胞瘤组织中 EGFR-ZNF263 信号成分的高表达与患者的预后不良相关。总之，我们的研究结果表明，SIX3 的表观遗传沉默受一种复杂且高度有序的致癌信号通路的控制，因此为胶质母细胞瘤的发生和进展提供了新的见解。
