Chemotherapy resistance of tumor cells is one of the major hurdles for bladder cancer treatment.The recent advances showed that some chemotherapeutics can trigger the activation of hypoxia-inducible factor(HIF)-1 inducing chemoresistance,while mechanistic understanding remain limited.In this study,we show that cisplatin induces the expression of miR-424,a direct HIF-1 target,in a HIF-1–dependent manner,leading to increased resistance to cisplatin induced apoptosis in vitro and reduced potency of cisplatin in the inhibition of tumor growth in a mouse xenograft model in vivo.Further studies indicate that miR-424 modulates drug resistance through downregulation of expressions of UNC5B and SIRT4,which are essential for intrinsic apoptosis pathway initiating by genotoxic treatment.Knockdown of UNC5B or SIRT4 expression inhibits intrinsic apoptosis pathway,which leads to cisplatin resistance,whereas rescue of UNC5B or SIRT4 expression in miR-424-expressing cells re-sensitizes bladder cancer cells to cisplatin-induced apoptosis.Furthermore,miR-424 levels are inversely correlated with UNC5B or SIRT4 expression in clinical bladder cancer samples.These results suggest that miR-424 maintains chemo-resistance as a potential molecular target for bladder cancer therapy via.HIF-1 under nonhypoxic conditions,and antagonizing miR-424 demonstrates therapeutic potential by sensitizing the malignancy to cisplatin treatment.