In this study, we identified a previously unappreciated role of SIRT4, which is a downstream target of α2δ1-mediated calcium signaling, in promoting the stem cell-like properties and invasiveness of HCC cells through deacetylating MCCC2 at K269 to form MCCC1/MCCC2 enzymatic complex with enhanced enzymatic activity. Here, MCCC1 is linked to hepatocellular carcinoma.