In the present study, we investigated the antitumor efficacy of TNKS small interfering RNA (siRNA) and NVP-TNKS656 in HCC cell lines, and we demonstrated that TNKS inhibition not only inhibited the proliferation of these cells but also suppressed their metastasis, invasion, and EMT phenotypic features. This evidence concerns the gene TNKS and hepatocellular carcinoma.