| Popis: |
Background The resistance mechanism to sorafenib in hepatocellular carcinoma (HCC) remains poorly understood. Recent evidence has demonstrated the enrichment of liver cancer stem cells (CSCs) as culprit for treatment resistance. In liver cancer development, SMYD3 epigenetically activates or overexpresses JAK/STAT3 pathway, epithelial-mesenchymal transition (EMT) pathway, SOX4 and MYC oncogenes, which play crucial roles in liver CSC. In this study, we demonstrate the novel role of SMYD3 in HCC resistance to sorafenib therapy. Methods We used sorafenib-resistant HCC in vitro and in vivo models to study the relationship between sorafenib resistance and SMYD3 expression. Chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR) were used to analyze the mechanism of SMYD3 regulation. Stemness and metastatic properties were investigated after treatment with SMYD3 depletion alone or in combination with sorafenib to evaluate the therapeutic effect on sorafenib resistance by in vitro and in vivo experiments. Result We identified overexpression of SMYD3 and subsequent increase of histone H3K4me3 as a novel pathway of acquired resistance to sorafenib in HCC. We also found that multiple SMYD3-mediated cancer-promoting genes exhibited up-regulation in sorafenib-resistant HCC cells and tumors. Inhibition of SMYD3 by a small-molecular inhibitor BCL121 or genetic means suppressed the transcription of SMYD3 target genes via the inhibition of the recruitment of H3K4me3-midifed histone tails to the core promoter regions of these genes. Restoration of wide-type SMYD3 protein in sorafenib-resistant cells with SMYD3 knockdown partly rescued the expression of target genes, while mutant SMYD3 did not. As such, modulating SMYD3 expression or activity in vitro and in vivo models inhibited the transcription output of target genes, mainly through SOX4, MYC, JAK1 and ZEB1 genes, and suppressed activation of their associated pathways, including EMT, JAK/STAT3, SOX4 and MYC pathway, and consequently weakened the stemness and metastatic properties of sorafenib-resistant cells in vitro and suppressed the relapse and metastasis of sorafenib-resistant tumors in vivo. Conclusion SMYD3 conferred sorafenib-resistant cells enhanced stemness and metastatic properties in HCC by epigenetically activating the expression of multiple cancer-promoting genes. SMYD3 could be a rational target for therapeutic intervention in sorafenib-resistant HCC. |
