Abstract
Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.