Long Noncoding RNA XIST Promotes Resistance to Lenvatinib in Hepatocellular Carcinoma Cells via Epigenetic Inhibition of NOD2

Background. Hepatocellular carcinoma (HCC) is a severe global health issue that still lacks of effective treatments. Lenvatinib is a novel tyrosine kinase inhibitor (TKI) that has been approved for the treatment of HCC. However, drug resistance is inevitable and limits the clinical application of lenvatinib. Till now, there is still little knowledge about the mechanisms under the resistance to lenvatinib in HCC. Long noncoding RNA (lncRNA) is a group of noncoding RNAs that play essential roles in various physiological activities including the chemoresistance. In the present study, through RNA sequencing, we discovered that lncRNA XIST was upregulated in HCC cells that was insensitive to lenvatinib. Mechanically, we found that lncXIST promotes lenvatinib resistance via activation of EZH2-NOD2-ERK axis in HCC cells. Our data suggest that targeting lncXIST/EZH2/NOD2/ERK axis might be a promising strategy to enhance the efficacy of lenvatinib against HCC cells.