FBXW7/GSK3β-mediated degradation of PRR11 inhibits RCC progression via oxidative DNA damage

In our previous study, we reported that proline-rich 11 (PRR11) expression is upregulated in renal cell carcinoma (RCC) and is involved in the regulation of cell cycle and apoptosis. Here, we continued to investigate the pro-carcinogenic role of PRR11 and found that PRR11 regulates oxidative DNA damage via activation of the AKT pathway, which promotes the proliferation and migration of RCC. Mechanistically, GSK3β recognizes and phosphorylates the CPD motif of PRR11, followed by FBXW7 binding to PRR11 and promoting its K48-linked ubiquitination and degradation via the CPD motif of PRR11. In addition, PRR11 can inhibit GSK3β activity via activation of AKT signaling, which in turn prevents the formation of PRR11-phosphorylated CPDs, thereby preventing FBXW7-mediated ubiquitination and degradation of PRR11. This PRR11-AKT interaction establishes a positive feedback loop that continually strengthens the expression of both and accelerates the progression of RCC. Overall, we reveal the specific mechanism by which FBXW7-GSK3β targets PRR11 degradation in RCC and PRR11 affects RCC proliferation and migration by regulating oxidative DNA damage, providing a new target and interventions for RCC therapy.