Abstract
Squamous cell carcinoma (SCC) is an aggressive epithelial malignancy, yet the molecular mechanisms underlying SCC development are elusive. ARID1A isfrequently mutated in various cancer types, but both mutation rates and expression levels of ARID1A are ubiquitously low in SCCs. Here, we reveal thatexcessive protein degradation mediated bytheubiquitin-proteasome system (UPS) contributes tothe loss of ARID1A expression in SCC. Weidentify 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.
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