TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3.
TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3.
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TRIM59 通过抑制 STAT3 的 TC45 去磷酸化促进胶质瘤发生
DOI：
10.1158/0008-5472.can-17-2774
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发表时间：
2018-04-01
期刊：
影响因子：
11.2
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Sang Y;Li Y;Song L;Alvarez AA;Zhang W;Lv D;Tang J;Liu F;Chang Z;Hatakeyama S;Hu B;Cheng SY;Feng H
异常表皮生长因子受体（EGFR）信号转导是胶质母细胞瘤（GBM）发病机制的常见驱动因素，然而，维持这一致癌途径的下游效应物仍不清楚。在这里，我们证明，三重基序包含蛋白59（TRIM 59）作为一个新的下游效应的EGFR信号通过调节STAT 3激活GBM。EGFR信号通过SOX 9导致TRIM 59上调，并增强了TRIM 59与核STAT 3之间的相互作用，这阻止了核形式的T细胞蛋白酪氨酸磷酸酶（TC 45）对STAT 3的去磷酸化，从而维持转录激活并促进肿瘤发生。沉默TRIM 59抑制GBM细胞和神经胶质瘤干细胞（GSC）的细胞增殖、迁移和原位异种移植脑肿瘤形成。对GBM患者样本的评估揭示了EGFR活化、TRIM 59表达、STAT 3磷酸化和不良炎症之间的关联。我们的研究将TRIM 59鉴定为致癌EGFR/STAT 3信号转导的新调节因子，并将其作为EGFR活化的GBM患者的潜在治疗靶点。
Aberrant epidermal growth factor receptor (EGFR) signaling is a common driver of glioblastoma (GBM) pathogenesis, however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells (GSCs). Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.