Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level. The most upregulated genes wereODAM,TRIM71, andIGDCC3, and the most downregulated wereSAA1,SAA2, andNNMT. Protein-protein interaction analysis identified ubiquitination as a key pathway dysregulated in HB.UBE2C, encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. Validation studies confirmed UBE2C immunostaining in 20 of 25 HB tumor specimensversus1 of 6 normal liver samples. The silencing ofUBE2Cin two HB cell models resulted in decreased cell viability. RNA sequencing analysis showed alterations in cell cycle regulation afterUBE2Cknockdown.UBE2Cexpression in HB correlated with inferior patient survival. We conclude thatUBE2Cmay hold prognostic utility in HB and that the ubiquitin pathway is a potential therapeutic target in this tumor.