Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes. Significance: The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.

中文翻译：

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TRAF4 维持 Caveolin-1 的去泛素化以驱动胶质母细胞瘤干性和替莫唑胺耐药

胶质母细胞瘤（GBM）是最常见的原发性成人脑肿瘤类型。GBM 中的胶质瘤干细胞 (GSC) 驻留和替莫唑胺 (TMZ) 耐药都会导致患者预后不佳。TRAF4是一种具有E3泛素连接酶活性的支架蛋白，最近被发现可促进多种恶性肿瘤的侵袭和转移，但TRAF4在GBM中的作用和功能仍有待确定。在这里，我们报告 TRAF4 在 GSC 中优先过表达，并且是 GBM 细胞中干细胞样特性和 TMZ 敏感性所必需的。TRAF4 与 Caveolin-1 (CAV1) 的 N 末端尾部特异性相互作用，CAV1 是 GBM 细胞致瘤性的重要贡献者。TRAF4 通过阻止 ZNRF1 介导的泛素化和促进 USP7 介导的去泛素化来调节 CAV1 稳定性，独立于其 E3 泛素连接酶催化活性。TRAF4 介导的 CAV1 稳定激活了促肿瘤发生 AKT/ERK1/2 信号传导，而该轴的破坏导致干性维持的缺陷。此外，TRAF4 和 CAV1 的表达呈正相关，并预测人类 GBM 样本中的不良预后。常见神经系统药物的筛选发现利培酮与 TRAF4 相互作用，利培酮治疗导致 TRAF4 和 CAV1 解离。重要的是，用利培酮对 TRAF4 进行药理抑制可有效抑制 GBM 的自我更新、消除致瘤性并逆转 TMZ 耐药性。全面的，TRAF4 介导的 CAV1 稳定可促进 GBM 的干性和 TMZ 耐药性，从而提供一种可以改善患者预后的治疗策略。意义：TRAF4/Caveolin-1 轴在胶质母细胞瘤恶性进展中发挥关键作用的鉴定为 TRAF4 在泛素信号传导中的功能提供了新的见解，并表明 TRAF4 作为潜在的治疗靶点。