Decreased expression of acetyl‐CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma

Abstract

Metastasis is a serious risk that may occur during the treatment of hepatocellular carcinoma (HCC), preventing many patients from being surgical candidates and contributing to poor prognosis. Hypoxia has been proved an important factor of metastasis through the epithelial–mesenchymal transition (EMT) pathway. Acetyl‐CoA synthase 2 (ACSS2) provides an acetyl group for the acetylation of hypoxia‐inducible factor (HIF)‐2α, and this epigenetic modification affects the activity of HIF‐2α and the subsequent EMT process. Here, we showed that ACSS2 expression was negatively correlated with HCC malignancy. Knockdown of ACSS2 increased the invasion and migration ability of HCC cells and promoted EMT without increasing the total protein level of HIF‐2α, even in hypoxic conditions. The immunoprecipitation assay revealed downregulated acetylation levels of HIF‐2α after ACSS2 knockdown in hypoxic conditions, which resulted in enhanced HIF‐2α activity. Finally, decreased expression of ACSS2 was found to be related to advanced stage and poor overall survival and disease‐free survival rates in a cohort of patients with HCC. In conclusion, ACSS2 plays an important role in the acetylation process of HIF‐2α, which effectively modifies the activity of HIF‐2α under hypoxic conditions and greatly impacts on the prognosis of patients with HCC.

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

“…In line with the role of acetyl-CoA in EMT induction, silencing of ACLY to abolish acetyl-CoA biosynthesis was sufficient to reverse EMT markers induced by ACC1 silencing, accompanied by blunted invasive capacity [26]. Contrary to the above results, ACSS2 overexpression in HCC was found to mediate acetylation of HIF-2α to inhibit EMT under hypoxia [35]. Therefore, the effect of acetyl-CoA is dependent on its target proteins and the tumor microenvironment.…”

Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis – Part 2: Acetate and ACSS2 in Health and Disease

“…Intriguingly, adult ACSS2 knockout mice appear phenotypically normal, however, they exhibit reduced tumor burdens in models of hepatic cancer ( Huang et al, 2018 ). Paradoxically, in other studies decreased expression of ACSS2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma ( Sun et al, 2017 ). In renal cell carcinoma, ACSS2 knockdown inhibited growth, migration, and invasion, whereas overexpression of ACSS2 enhanced these effects, implying that ACSS2 increases renal cell tumor aggressiveness ( Zhang et al, 2018 ).…”

Lipid metabolism reprogramming and its potential targets in cancer

“…When each isoform was genetically knocked down in HepG2 cells, only ACSS2 down-regulation dramatically suppressed acetate-mediated lipid synthesis and histone modification [ 72 ]. In fact, ACSS2 expression correlates inversely with overall survival in patients with triple-negative breast cancer, liver cancer, glioma or lung cancer [ 72 , 73 , 168 , 169 ]. Studies with patient-derived glioblastoma xenografts have shown that acetate contributes to acetyl-CoA synthesis in tumors [ 73 ].…”