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Gene expression profiling for circPETH overexpression and knockout

ABSTRACT: Metabolic reprogramming fuels cancer cell metastasis and remodels immunosuppressive tumor microenvironment (TME). We report here that a circRNA packaged by extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, circPETH, facilitates glycolysis and metastasis of HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in m6A-driven manner, promotes the PKM2-catalyzed ALDOA-S36 phosphorylation via MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by elevating the HuR-dependent SLC43A2-mRNA stability and stimulating the deficiency of methionine and leucine in cytotoxic CD8+ T cells. Importantly, we successfully identified a novel small molecule, Norathyriol, by virtual and experimental screening as an effective inhibitor targeting MEG pocket on circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated metabolic and metastatic phenotypes of HCC cells, improves anti-PD1 efficacy and boosts cytotoxic CD8+ T cells function. Our findings determine Norathyriol as a promising anti-HCC agent, and contribute to overcoming the resistance of advanced HCC to immune checkpoint blockades (ICBs) therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242016 | GEO | 2024/08/29

REPOSITORIES: GEO

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Gene expression profiling of CD8+ T cells in the Norathyriol versus PBS-treated co-culture system

Project description:Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that a circRNA, circPETH, packaged by extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis of recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in a m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by elevating HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, by virtual and experimental screening, we found that the novel small-molecule Norathyriol was an effective inhibitor that targets the MEG pocket on circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes for HCC cells, increases anti-PD1 efficacy and boosts cytotoxic CD8+ T-cell function. Our findings determine Norathyriol as a promising anti-HCC agent that contributes to the attenuation of advanced HCC resistance to immune checkpoint blocker (ICB) therapies.

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