In the present study, mechanistic investigations identified that DEPDC1 overexpression promoted HCC cell viability and chemotherapy resistance by activating JNK signaling pathway, while DEPDC1 knocked suppressed cell viability and chemotherapy resistance by down-regulating JNK pathway; meanwhile, JNK specific inhibitor SP600125 was observed to have similar effects to DEPDC1 depletion, indicating that JNK pathway mediated the oncogenic effects of DEPDC1 in HCC. This evidence concerns the gene MAPK8 and hepatocellular carcinoma.