Recurrent ZNF83-E293V mutation promotes bladder cancer progression through NF-κB pathway via transcriptional dysregulation of S100A8

Abstract Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations bring about large variation in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of the next-generation sequencing data of 99 UC patients, we identified 18% of cases had recurrent somatic mutations in a zinc finger protein gene ZNF83. ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation p. E293V in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wildtype ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated NF-κB more potently than the wildtype protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established foundation for using ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.