USP1 activates the Wnt/β-catenin pathway by deubiquitinating KRT17, thereby facilitating thyroid cancer proliferation

Post-translational modification through ubiquitination is widely acknowledged for its pivotal regulatory role in tumor onset and progression. Ubiquitin ligases and deubiquitinases can modulate tumor advancement by impacting the expression of key proteins. Nonetheless, the precise contribution of ubiquitination and deubiquitinases in the onset of thyroid cancer (TC) remains to be comprehensively understood. Initially, Weighted Gene Co-expression Network Analysis (WGCNA) revealed the deubiquitinase USP1 as closely associated with TC and protein ubiquitination. Subsequently, our findings demonstrated the aberrant upregulation of USP1 expression in clinical TC samples. Moreover, interference with USP1 expression inhibited the proliferative ability of TC cells in vitro by colony formation and CCK8 assays. Notably, our findings have revealed that USP1 facilitates the proliferation of TC by modulating the Wnt/β-catenin pathway. Further, we identified KRT17 as a critical factor in the USP1-mediated Wnt/β-catenin pathway. Next, we validated that USP1 directly interacted with KRT17 and deubiquitinated it. Ultimately, we discovered that parthenolide exerted inhibitory effects on TC proliferation both in vivo and in vitro by modulating the USP1-KRT17-Wnt/β-catenin axis. To sum up, Our findings offer compelling evidence that underscores the pivotal role of USP1 in promoting TC proliferation. This is accomplished by stabilizing KRT17 expression through deubiquitination, which in turn activates the Wnt/β-catenin pathway. These results provide novel insights into potential therapeutic targets for TC treatment.