TRIM32/USP11 Balances ARID1A Stability and the Oncogenic/Tumor-Suppressive Status of Squamous Cell Carcinoma

• Main Authors: Qingyu Luo, Xiaowei Wu, Yabing Nan, Wan Chang, Pengfei Zhao, Yiping Zhang, Dan Su, Zhihua Liu
• Format: Article
• Language: English
• Published: Elsevier 2020-01-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719316675

Summary: 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 a mechanism underlying ARID1A loss and propose an important role for the TRIM32/USP11-ARID1A-SDC2 axis in SCC. : Luo et al. show that excessive degradation of ARID1A by the ubiquitin-proteasome system promotes SCC progression by activating SDC2. TRIM32 and USP11 are the key E3 ligase and deubiquitinase that antagonize each other to control ARID1A stability and the oncogenic or tumor-suppressive status of SCC. Keywords: ARID1A, TRIM32, USP11, ubiquitination, deubiquitination, squamous cell carcinoma, tumor suppressor