Here, we identified HDAC6 as the predominant α-tubulin deacetylase in HCC cells: HDAC6 inhibition or depletion enhanced microtubule acetylation and promoted migration and invasion in HCC cells, whereas the protein level and distribution of acetylated microtubules were not obviously affected by sirtuin 2 suppression. Here, HDAC6 is linked to hepatocellular carcinoma.