Isoprenylcysteine carboxylmethyltransferase (Icmt) which catalyzes the final step of prenylation of many oncoproteins, such as Ras. Despite studies on Icmt and its regulation in biological activities of various cancers, little is known on the expression, function and mechanisms of the impact of Icmt on hepatocellular carcinoma (HCC). We report here the findings that Icmt is critical for HCC growth, migration, survival and chemoresistance by multiple oncogenic pathways. Expression analysis on primary patient and cell line samples demonstrated that Icmt protein level was significantly higher in the majority (similar to 70%) of HCC tissues and cells than corresponding normal counterparts. Icmt depletion inhibited growth, survival and migration in HCC cells, and augmented the inhibitory effects of doxorubicin. Consistently, Icmt also inhibited growth, and migration, and induced apoptosis in HCC cells that are resistant to doxorubicin. In contrast, Icmt overexpression promoted growth and migration in normal liver cells. Mechanistically, Icmt inhibition suppressed Ras/Raf/Mek/Erk signaling and epithelial-mesenchymal transition (EMT) in HCC cells. Several different approaches demonstrated that Icmt was critical for HCC biological activities with the predominant role in cell response to chemotherapy. This previously unappreciated function of Icmt can be targeted to enhance chemotherapy in particular those HCC patients with high Icmt expression. (C) 2019 Elsevier Inc. All rights reserved.