CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation.
CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation.
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CHIP/STUB1 泛素连接酶通过促进 ErbB2 的早期生物合成后降解而发挥其负调节作用
DOI：
10.3390/cancers13163936
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发表时间：
2021-08-04
期刊：
影响因子：
5.2
通讯作者：
Band H
中科院分区：
文献类型：
--
作者：
Luan H;Bailey TA;Clubb RJ;Mohapatra BC;Bhat AM;Chakraborty S;Islam N;Mushtaq I;Storck MD;Raja SM;Band V;Band H
ErbB 2/HER 2受体过表达导致多达四分之一的乳腺癌。ErbB 2生物学的一个方面是知之甚少的是它如何在内质网（ER）中生物合成后到达细胞表面。在这里，作者表明，CHIP（HSC 70-Interacting protein的C-末端）/STUB 1（STIP 1-homologous U-Box containing protein 1）蛋白靶向新合成的ErbB 2，用于ER和高尔基体中的泛素/蛋白酶体依赖性降解，确定了一种负调控ErbB 2细胞表面表达的新机制。这些发现为CHIP表达的频繁缺失提供了一种解释，即ErbB 2过表达的乳腺癌。作者进一步表明，具有低CHIP表达的ErbB 2过表达乳腺癌细胞表现出更高的ER应激诱导，并且ER应激诱导抗癌药物Bortezumab与ErbB 2靶向人源化抗体曲妥珠单抗协同作用以抑制癌细胞增殖。这些新的见解表明，减少CHIP表达可能指定ErbB 2过表达乳腺癌适合曲妥珠单抗和ER应激诱导剂的联合治疗。摘要表皮生长因子受体（EGFR）家族成员ErbB 2（HER 2）的过表达导致了高达25%的浸润性乳腺癌的发生。ErbB 2在细胞表面的表达是肿瘤发生所必需的，但其在内质网中生物合成后确保过表达ErbB 2的最佳细胞表面展示的机制知之甚少。ErbB 2依赖于与HSP 90分子伴侣的连续缔合以实现其稳定性和作为致癌驱动剂的功能。在这里，我们使用敲低和过表达的研究表明，HSP 90/HSC 70相互作用的负辅伴侣CHIP（HSC 70相互作用蛋白的C末端）/STUB 1（STIP 1同源的含U盒蛋白1）靶向新合成的HSP 90/HSC 70相关的ErbB 2，用于内质网和高尔基体中的泛素/蛋白酶体依赖性降解，从而鉴定了负调节乳腺癌细胞中细胞表面ErbB 2水平的新机制，这与先前报道的ErbB 2过表达乳腺癌中CHIP表达的频繁丧失一致。CHIP低表达的ErbB 2过表达乳腺癌细胞表现出更高的内质网应激诱导。因此，内质网应激诱导抗癌药物Bortezumab与ErbB 2靶向人源化抗体曲妥珠单抗组合显示出对ErbB 2过表达乳腺癌细胞增殖的协同抑制。我们的研究结果揭示了控制过表达ErbB 2表面表达的机制的新见解，并表明CHIP表达减少可能指定ErbB 2过表达乳腺癌适合曲妥珠单抗和ER应激诱导剂联合治疗。
Simple Summary Overexpressed ErbB2/HER2 receptor drives up to a quarter of breast cancers. One aspect of ErbB2 biology that is poorly understood is how it reaches the cell surface following biosynthesis in the endoplasmic reticulum (ER). Here, the authors show that the CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) protein targets the newly synthesized ErbB2 for ubiquitin/proteasome-dependent degradation in the ER and Golgi, identifying a novel mechanism that negatively regulates cell surface expression of ErbB2. These findings provide one explanation for frequent loss of CHIP expression is ErbB2-overexpressing breast cancers. The authors further show that ErbB2-overexpressing breast cancer cells with low CHIP expression exhibit higher ER stress inducibility, and ER stress-inducing anticancer drug Bortezomib synergizes with ErbB2-targeted humanized antibody Trastuzumab to inhibit cancer cell proliferation. These new insights suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents. Abstract Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.
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