Abstract 1491: Delineating the oncogenic mechanisms of NAT10 in hepatocellular carcinoma

Abstract

Protein synthesis is often dysregulated in cancer, highlighting the regulatory mechanisms of translation as potential targets for cancer treatment. With more than 140 chemical modifications of RNA, the epitranscriptome is a central mechanism in regulating protein synthesis. Remarkably, the epitranscriptome is often altered in cancerous tumors and under stress conditions such as reactive oxygen species (ROS) and anti-tumor therapies. For instance, N-acetyltransferase 10 (NAT10), the enzyme responsible for acetylating cytidines (N4-acetylcytidine or ac4C) in RNA, is highly overexpressed in cancers such as Hepatocellular Carcinoma (HCC). Of significant relevance to cancer, NAT10 is considered an oncogenic driver in fatty acid-induced HCC. Hence, this project aims to characterize the underlying oncogenic mechanisms of the NAT10/ac4C axis. Our data indicate that NAT10 and RNA acetylation levels are altered in response to fatty acids, ROS, and chemotherapeutic drugs. Likewise, we observed altered subcellular localization of NAT10 and ac4C in response to ROS and chemotherapeutic drugs. Building on our previous findings that NAT10-catalyzed ac4C promotes translation efficiency, our model stipulates that subcellular redistribution of the RNA acetyltransferase complexes enhances cell cycle progression, cancer cell proliferation, and cellular resilience by fine-tuning the translation of cancer driver genes. Collectively, our findings advance our understanding of how NAT10 promotes cancer growth while providing the mechanistic basis to target NAT10 for therapeutic purposes. Citation Format: Emmely A. Patrasso, Sweta P. Raikundalia, Daniel Arango. Delineating the oncogenic mechanisms of NAT10 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1491.