ATP citrate lyase promotes the progression of hepatocellular carcinoma by activating the REGγ-proteasome pathway

The search for novel tumor biomarkers and targets is of significant importance for the early clinical diagnosis and treatment of Hepatocellular Carcinoma (HCC). The mechanisms by which ATP citrate lyase (ACLY) promotes HCC progression remain unclear, and the connection between ACLY and REG gamma has not been reported in the literature. In vitro, we will perform overexpression/knockdown of ACLY or overexpression/knockdown of REG gamma to investigate the impact of ACLY on HCC cells and its underlying mechanisms. In vivo, we will establish mouse tumor models with overexpression/knockdown of ACLY or overexpression/knockdown of REG gamma to study the effect of ACLY on mouse tumors and its mechanisms. Firstly, ACLY overexpression upregulated REG gamma expression and activated the REG gamma-proteasome pathway, leading to changes in the expression of downstream signaling pathway proteins. This promoted HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Secondly, ACLY overexpression increased acetyl-CoA production, upregulated the acetylation level of the REG gamma promoter region histone H3K27ac, and subsequently induced REG gamma expression. Lastly, enhanced acetylation of the REG gamma promoter region histone H3K27ac resulted in upregulated REG gamma expression, activation of the REG gamma-proteasome pathway, changes in downstream signaling pathway protein expression, and promotion of HCC cell proliferation, invasion, and migration in vitro, as well as tumor growth and metastasis in vivo. Conversely, REG gamma knockdown reversed these effects. ACLY and REG gamma may serve as potential biomarkers and clinical therapeutic targets for HCC.