State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, Department of Physiology, China Pharmaceutical University, Nanjing, P.R. China.
Department of Neurosurgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, P.R. China.
Cancer Res. 2022 Oct 4;82(19):3573-3587. doi: 10.1158/0008-5472.CAN-21-3882.
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.
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.
胶质母细胞瘤（GBM）是最常见的原发性成人脑肿瘤。GBM 中的神经胶质瘤干细胞（GSC）定植和替莫唑胺（TMZ）耐药均导致患者预后不良。TRAF4 是一种支架蛋白，具有 E3 泛素连接酶活性，最近发现它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 GSCs 中优先过表达，并且需要 GBM 细胞的干细胞样特性和 TMZ 敏感性。TRAF4 特异性与 Cavin-1（CAV1）的 N 端尾巴相互作用，CAV1 是 GBM 细胞致瘤性的重要贡献者。TRAF4 通过防止 ZNRF1 介导的泛素化和独立于其 E3 泛素连接酶催化活性促进 USP7 介导的去泛素化来调节 CAV1 的稳定性。TRAF4 介导的 CAV1 稳定激活了促肿瘤的 AKT/ERK1/2 信号，而该轴的破坏导致干细胞维持缺陷。此外，TRAF4 和 CAV1 的表达呈正相关，并预测了人类 GBM 样本的不良预后。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 的解离。重要的是，用利培酮抑制 TRAF4 可有效抑制 GBM 的自我更新、消除致瘤性并逆转 TMZ 耐药性。总的来说，TRAF4 介导的 CAV1 稳定促进了 GBM 的干细胞特性和 TMZ 耐药性，为 TRAF4 在泛素信号中的功能提供了新的见解，并提示 TRAF4 可能成为一种潜在的治疗靶点。
鉴定出 TRAF4/Caveolin-1 轴在胶质母细胞瘤恶性进展中起关键作用，为 TRAF4 在泛素信号中的功能提供了新的见解，并提示 TRAF4 可能成为一种潜在的治疗靶点。
