TRIM32/USP11 Balances ARID1A Stability and the Oncogenic/Tumor-Suppressive Status of Squamous Cell Carcinoma
TRIM32/USP11 Balances ARID1A Stability and the Oncogenic/Tumor-Suppressive Status of Squamous Cell Carcinoma
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DOI：
10.1016/j.celrep.2019.12.017
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发表时间：
2020-01-07
期刊：
影响因子：
8.8
通讯作者：
Liu, Zhihua
中科院分区：
文献类型：
--
作者：
Luo, Qingyu;Wu, Xiaowei;Liu, Zhihua
鳞状细胞癌（SCC）是一种侵袭性上皮恶性肿瘤，但SCC发展的分子机制是难以捉摸的。ARID 1A在各种癌症类型中经常发生突变，但ARID 1A的突变率和表达水平在SCC中普遍较低。在这里，我们揭示了过度的蛋白质降解介导的泛素-蛋白酶体系统（UPS）有助于在SCC中的ARID 1A表达的损失。我们确定E3连接酶TRIM 32和去泛素化酶USP 11在控制ARID 1A稳定性中起关键作用。TRIM 32耗竭通过稳定ARID 1A抑制SCC细胞增殖、转移和化学抗性，而USP 11耗竭通过促进ARID 1A降解促进SCC发展。我们发现，syndecan-2（SDC 2）是ARID 1A和USP 11的下游靶点，SDC 2缺失消除了ARID 1A缺失的致癌功能。总之，我们的数据揭示了UPS介导的蛋白质降解作为ARID 1A丢失的潜在机制，并提出了TRIM 32/USP 11-ARID 1A-SDC 2轴在SCC中的重要作用。
Squamous cell carcinoma (SCC) is an aggressive epithelial malignancy, yet the molecular mechanisms underlying SCC development are elusive. ARID1A is frequently mutated in various cancer types, but both mutation rates and expression levels of ARID1A are ubiquitously low in SCCs. Here, we reveal that excessive protein degradation mediated by the ubiquitin-proteasome system (UPS) contributes to the loss of ARID1A expression in SCC. We identify that the E3 ligase TRIM32 and the deubiquitinase USP11 play key roles in controlling ARID1A stability. TRIM32 depletion inhibits SCC cell proliferation, metastasis, and chemoresistance by stabilizing ARID1A, while USP11 depletion promotes SCC development by promoting ARID1A degradation. We show that syndecan-2 (SDC2) is the downstream target of both ARID1A and USP11 and that SDC2 depletion abolishes the oncogenic function of ARID1A loss. In summary, our data reveal UPS-mediated protein degradation as amechanism underlying ARID1A loss and propose an important role for the TRIM32/USP11-ARID1A-SDC2 axis in SCC.