NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer

by Selleckchem | Jun 19 2023

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.

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The passage describes a study on the role of a specific RNA modification called N4-acetylcytidine (ac4C) and its writer enzyme N-acetyltransferase 10 (NAT10) in bladder cancer. The researchers found that the ac4C modification is induced when bladder cancer cells are treated with the chemotherapy drug cisplatin and is associated with chemoresistance.

The study showed that NAT10 promotes cisplatin chemoresistance in bladder cancer cells both in laboratory settings (in vitro) and in living organisms (in vivo) by enhancing DNA damage repair (DDR). The researchers discovered that NAT10 binds to and stabilizes the mRNA of a gene called AHNAK, protecting it from degradation by exonucleases. AHNAK, in turn, plays a crucial role in DDR, which is necessary for the cancer cells to repair DNA damage caused by cisplatin treatment and survive.

The clinical relevance of these findings was investigated as well. The researchers found that NAT10 overexpression in bladder cancer patients was associated with chemoresistance, cancer recurrence, and worse clinical outcomes. This suggests that NAT10 may serve as a biomarker for predicting patient response to cisplatin treatment and prognosis.

The study also explored the molecular mechanisms underlying NAT10 regulation. It was discovered that cisplatin treatment activates a signaling pathway called NFκB, which in turn upregulates NAT10 expression. The NFκB p65 protein directly binds to the NAT10 gene promoter, thereby promoting its transcription and increasing NAT10 levels.

Finally, the researchers investigated the therapeutic potential of targeting NAT10 to overcome cisplatin resistance in bladder cancer. They used a pharmacological inhibitor called Remodelin to inhibit NAT10 activity. This inhibition sensitized bladder cancer organoids (miniature models of tumors grown in the laboratory) and mouse xenografts (transplanted tumors in mice) to cisplatin treatment, suggesting that targeting NAT10 could be a promising strategy to enhance the effectiveness of cisplatin chemotherapy in bladder cancer.

In summary, this study provides insights into the role of NAT10-mediated mRNA stabilization in bladder cancer and suggests that NAT10 could be a therapeutic target for overcoming cisplatin resistance in this type of cancer.