Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the 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 brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and pro- gression of UC is essential. Through deep analysis of next-gen- eration sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (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 wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V acti- vated nuclear factor kB (NF-kB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-kB inhibitors could pharmaco- logically 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 a foundation for using the ZNF83- E293V mutation as a predictive biomarker of therapeutic response from NF-kB inhibitors.