IGF2BP3 promotes the proliferation and cisplatin resistance of bladder cancer by enhancing the mRNA stability of CDK6 in an m6A dependent manner

Cisplatin-based chemotherapy is a primary treatment for bladder cancer, yet the development of chemoresistance poses a significant therapeutic challenge. Insulin-like growth factor II mRNA binding protein 3 (IGF2BP3) is an RNA-binding protein and a key m6A reader that regulates various cancers through m6A-dependent mechanisms. However, its role in chemotherapy resistance in bladder cancer remains unclear. Our in vivo and in vitro experiments identified IGF2BP3 as a key regulator of cisplatin resistance in bladder cancer. We demonstrated that IGF2BP3 enhances the stability of CDK6 mRNA in an m6A-dependent manner, leading to increased CDK6 expression. This, in turn, promoted tumor cell proliferation and resistance to cisplatin chemotherapy. Moreover, we showed that the CDK6 inhibitor palbociclib effectively suppresses the pro-growth and chemoresistant effects induced by IGF2BP3 overexpression. These results suggested that the IGF2BP3/m6A/CDK6 axis plays a pivotal role in bladder cancer progression and chemoresistance, and that targeting this pathway with CDK6 inhibitors such as palbociclib may offer a promising therapeutic strategy for overcoming cisplatin resistance in bladder cancer.