Nature Communications|上海交大附属仁济医院冯海忠研究组揭示胶质母细胞瘤新机制

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iNature：表皮生长因子受体（EGFR）的异常扩增和突变是胶质母细胞瘤（GBM）中最常见的致癌事件，但是怎么促进侵袭性发病机制尚不清楚。在这里，冯海忠研究组确定在临床GBM标本中，非经典的H3K23ac结合蛋白TRIM24被上调，同时TRIM24也是EGFR驱动的肿瘤发生所必需的。在多种胶质瘤细胞系和患者衍生的神经胶质瘤干细胞（GSCs）中，EGFR信号传导促进H3K23乙酰化并与TRIM24缔合。因此，TRIM24作为转录共激活剂并募集STAT3，导致稳定的STAT3-染色质相互作用和随后的STAT3下游信号传导的激活，由此增强EGFR驱动的肿瘤发生。研究结果揭示了TRIM24作为致癌EGFR信号传导一个关键调控因子，并建议TRIM24作为与EGFR激活相关的GBM的潜在治疗靶标，对于以后的临床应用有很大潜力。

Abstract:

Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.

原文下载：

https://pan.baidu.com/s/1skOx06L（可直接下载，仅用于教育，不得商用）

原文链接

https://www.nature.com/articles/s41467-017-01731-w

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