Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer.

Background/Aims Aberrant c-Jun N-terminal kinase(JNK) activation has been linked to hepatocellular carcinoma ( HCC) in mouse models. It remains unclear whether JNK activation plays an important role in human HCCand, if so, how JNK signaling contributes to the initiation or progression of HCC. Methods The JNK activation, global gene expression, and the status of histone H3methylations were measured in 31 primary human hepatocellular carcinoma ( HCC) samples paired with the adjacent non-cancerous (ANC) tissues. Results Enhanced JNK1 activation was noted in 17 out of 31 HCCsamples (55%) relative to the corresponding ANC tissues, whereas JNK2 activation was roughly equal between HCCand ANC tissues. This enhancement in JNK1 activation is associated with an increased tumor size and a lack of encapsulation of the tumors. In addition, an association of JNK1 activation with the histone H3lysines 4 and 9 tri-methylation was observed in the HCCtissues, which leads to an elevated expression of genes regulating cell growth and a decreased expression of the genes for cell differentiation and the p450 family members in HCC. Conclusions These results, thus, suggest that JNK1 plays important roles in the development of human HCCpartially through the epigenetic mechanisms.