Recurrent mutation of zinc finger protein 83 increased tumor progression via NF-KB signaling through transcriptional dysregulation of S100A8 in human urinary bladder cancer

Abstract

Urinary bladder cancer (UBC) ranks the 4th commonest cancer in male and 9th commonest in female around the world. About 81,400 patients were newly diagnosed of UBC and 17,980 patients succumbed to this disease in the United States in 2020.

Clinically, the predominant form of urinary bladder cancer is urothelial carcinoma (UC), which is formerly called transitional cell carcinoma (TCC), representing 90% of cases. Though the causes are still not clear yet, the major risks for bladder cancer are tobacco smoking, bladder inflammation, toxic chemicals exposure, genetic mutations and other factors. UCs consist of two main pathological subtypes, one is low-grade or non-muscle-invasive and the other is high-grade or muscle-invasive, which have drastically different behaviors. Moreover, the mortality rates keep increasing for past decades, for lack of early disease diagnosis targets with precision and sensitivity. Therefore, it is essential to discover suitable biomarkers for effective diagnosis and therapies of this disease.

As one of the important hallmarks of cancer, genomic mutations displayed in UC is prevalent and contribute greatly to the progression of UC. In our earlier work, the next-generation sequencing in tumors from 99 Chinese patients with UC was performed, which revealed that 57 of the 99 tumors (58%) had somatic mutations in genes involved in chromatin modifications, including UTX, CREBBP, EP300, NCOR1, CHD6, ARID1A and MLL-MLL3. 13 genes with significant mutations which have not previously been reported in TCCs, such as STAG2, ESPL1 and NIPBL, were observed. With an in-depth analysis on the sequencing data, a novel gene ZNF83 was found to harbor genetic alterations in 18% of 99 patients in all. Being a member of C2H2-type zinc-finger proteins, ZNF83 possesses the structures as well as functions in common with other family members. However, to the best of our knowledge, little research has been done about ZNF83 in any cancer so far.

To determine the biological function and molecular mechanism of ZNF83 in UC progression, I firstly verified the mutation status of ZNF83 by sanger sequence in additional 33 UC samples. The functional characterizations of ZNF83 were further investigated in UC cells and xenograft models. The results showed that somatic mutations of ZNF83 were frequently detected in UC and correlated with poor prognosis. ZNF83-E293V activated NF-κB more potently than the wildtype protein owing to its decreased transcriptional repression for S100A8. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wildtype ZNF83. The treatment of NF-κB inhibitors suppressed the E293V mutation of ZNF83 induced tumor growth in vivo.

The present study reveals that recurrent loss-of-function mutation E293V of ZNF83 promoted UC progression through NF-κB signaling pathway. The E293V mutation of ZNF83 has the potential to be therapeutic predictor of the responses from NF-κB inhibitors in treating human urothelial bladder cancer, which is worth further investigation.