Investigating the mechanistic role of RNA Acetylation and Oxidation in Hepatocellular Carcinoma

Project: Research project

Project Details

Description

We propose investigating how NAT10 promotes HCC growth and the response of hepatic cells to stress. The hypothesis of this proposal stipulates that NAT10-catalyzed RNA acetylation rewires translation in HCC, providing a cancer-competent proteome that promotes cell proliferation and resiliency to stress conditions. We will address this hypothesis under two specific aims. Aim 1 will identify the molecular mechanisms by which NAT10 promotes HCC cell proliferation using unbiased deep mutagenesis experiments, competitive proliferation assays, and transcriptomics methods in HCC cell lines and mouse xenografts. Given that NAT10 is particularly oncogenic in the context of fatty liver disease, aim 2 will delineate the mechanisms by which RNA acetylation regulates the cellular response to lipid accumulation and oxidative stress. We will use a model of fatty acid-induced oxidative stress in combination with transcriptomics assays and in vitro approaches to study the relationship between RNA acetylation, RNA oxidation, and mRNA translation in response to cellular stress.  The studies proposed in this project will advance our understanding of how NAT10 promotes HCC oncogenesis. This knowledge will provide the mechanistic basis to design and identify NAT10 inhibitors with high specificity and efficacy while reducing non-specific effects. In alignment with the V Foundation’s mission, our long-term goal is to harness such mechanisms to generate new tools and therapies to fight cancer and save lives. 
StatusActive
Effective start/end date10/1/2210/1/24

Funding

  • V Foundation for Cancer Research (V2022-016)

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