Epitranscriptomic RNA modifications constitute a critical gene regulatory component that can affect cancer progression. Among these, the RNA N4-acetylcytidine (ac4C) modification, which is mediated by the ac4C writer N-acetyltransferase 10 (NAT10), regulates the stabilization of mRNA.
Here, we identified that the ac4C modification is induced upon cisplatin treatment and correlates with chemoresistance in bladder cancer. Both in vitro and in vivo, NAT10 promoted cisplatin chemoresistance in bladder cancer cells by enhancing DNA damage repair (DDR). Mechanistically, NAT10 bound and stabilized AHNAK mRNA by protecting it from exonucleases, and AHNAK-mediated DDR was required for NAT10-induced cisplatin resistance. Clinically, NAT10 overexpression was associated with chemoresistance, recurrence, and worse clinical outcome in patients with bladder cancer. Cisplatin-induced NFκB signaling activation was required for the upregulation of NAT10 expression, and NFκB p65 directly bound to the NAT10 promoter to activate transcription. Moreover, pharmacological inhibition of NAT10 with Remodelin sensitized bladder cancer organoids and mouse xenografts to cisplatin. Overall, the present study uncovered a mechanism of NAT10-mediated mRNA stabilization in bladder cancer, laying the foundation for NAT10 as a therapeutic target to overcome cisplatin resistance in bladder cancer.
The mRNA ac4C writer NAT10 stimulates DNA damage repair to promote cisplatin chemoresistance in bladder cancer, identifying NAT10 inhibition as a potential therapeutic approach to enhance cisplatin sensitivity.
Cancer research. 2023 May 15 [Epub]
Ruihui Xie, Liang Cheng, Ming Huang, Lin Huang, Ziyue Chen, Qiang Zhang, Hong Li, Junlin Lu, Hongjin Wang, Qianghua Zhou, Jian Huang, Xu Chen, Tianxin Lin
Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China., Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China., Jingke BioMed Laboratory, Guangzhou Jingke Biotech Group, Guangzhou, P. R. China.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36939377