HSP90-CDC37 functions as a chaperone for the oncogenic FGFR3-TACC3 fusion.
HSP90-CDC37 functions as a chaperone for the oncogenic FGFR3-TACC3 fusion.
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HSP90-CDC37 作为致癌 FGFR3-TACC3 融合蛋白的伴侣。
DOI：
10.1016/j.ymthe.2022.02.009
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发表时间：
2022-02
影响因子：
12.4
通讯作者：
Zhang Wei
中科院分区：
文献类型：
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作者：
Li Tao;Mehraein-Ghomi Farideh;Forbes M Elizabeth;Namjoshi Sanjeev V;Ballard E Ashley;Song Qianqian;Chou Ping-Chieh;Wang Xuya;Parker Kerrigan Brittany C;Lang Frederick F;Lesser Glenn;Debinski Waldemar;Yang Xuejun;Zhang Wei
fgfr3 - tacc3 （F3-T3）融合基因在胶质母细胞瘤和膀胱癌中被发现是一种致癌分子，随后在许多癌症类型中被发现。值得注意的是，F3-T3在同时放疗和替莫唑胺（TMZ）治疗的未治疗和匹配的复发胶质母细胞瘤中均被发现高表达，这表明靶向F3-T3是一种有效的治疗策略。在这里，我们发现F3-T3蛋白是热休克蛋白90 （HSP90）的客户端，与细胞分裂周期37 （CDC37）形成三元配合物。HSP90或CDC37的缺失会破坏三元复合物的形成，使糖基化的F3-T3不稳定，从而抑制F3-T3的致癌活性。含有F3-T3的胶质瘤对TMZ化疗具有耐药性。HSP90抑制剂通过抑制F3-T3的激活和增强TMZ诱导的DNA损伤，使F3-T3胶质瘤细胞对TMZ敏感。这些结果表明F3-T3的致癌功能依赖于HSP90伴侣系统，并为靶向癌症中这种遗传畸变提供了新的临床选择。
TheFGFR3-TACC3(F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably,F3-T3was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemotherapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.