2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Bladder Cancer

The Role of Epitranscriptomic Regulator NAT10 in Bladder Cancer Chemoresistance - Expert Commentary

Post-transcriptional RNA modifications that underlie gene regulation have been implicated in severe diseases. The N-acetyltransferase 10 (NAT10), the only known human enzyme that catalyzes the formation of the N4-acetylcytidine (ac4C) mark, contributes to the epithelial-to-mesenchymal (EMT) transition of cancer cells. Xie et al. characterized the role of these epi-transcriptomic processes in bladder cancer and investigated their role in modulating sensitivity to cisplatin-based chemotherapy.

Upon treating bladder cancer cell lines with cisplatin, the researchers observed a global and dose-dependent increase in ac4C presence. Interestingly, this effect was particularly strong in chemoresistant patient tissue samples relative to sensitive samples. In parallel, NAT10 was upregulated in the resistant tumors. The ac4C modification was mainly localized to protein-coding genes and in mRNA. Depletion of NAT10 in bladder cancer cells led to a significant increase in apoptosis and a decrease in viability and cisplatin resistance. These effects were found to be linked to an increase in DNA damage repair pathways. Mice injected with NAT10-depleted cancer xenografts and treated with cisplatin had smaller tumors than treated mice injected with wild-type cancer cells.

Researchers identified a direct correlation between the expression of NAT10 and AHNAK. Further experiments revealed that NAT10 stabilizes AHNAK mRNA, and this interaction was central to the ability of NAT10 to induce chemoresistance. Further, bladder cancer patients with high AHNAK or NAT10 exhibited poorer prognosis and survival. NAT10 expression was also higher in chemotherapy non-responsive sites than in responsive sites and in post-chemotherapy tumors compared to pre-treatment tumors. In terms of mechanisms affecting NAT10 expression, p65, a protein that is part of the NF-kB pathway, was found to bind to the NAT10 promoter directly. Remodelin, a NAT10 inhibitor reduced cell viability and enhanced sensitivity of bladder cancer cells to chemotherapy. This was confirmed in vivo, as tumor weight and volume were smaller after remodeling treatment.

This novel study shows that the potential of epitranscriptomic mechanisms, including NAT10, in cisplatin resistance. are needed to identify additional epigenetic modifications that may play roles in disease.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

  1. Xie R, Cheng L, Huang M, et al. NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer. Cancer Res. 2023;83(10):1666-1683. 
Read the Abstract