NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer.
Cancer Res
; 83(10): 1666-1683, 2023 05 15.
Article
en En
| MEDLINE
| ID: mdl-36939377
ABSTRACT
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. SIGNIFICANCE:
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vejiga Urinaria
/
Cisplatino
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2023
Tipo del documento:
Article