USP22-JMJD8 axis promotes Lenvatinib resistance in hepatocellular carcinoma

Lenvatinib is the first-line treatment for patients with advanced HCC, however, drug resistance cannot be avoided during the treatment process, limiting the efficacy of Lenvatinib. We constructed drug-resistant HCC cells by gradually increasing the dose of Lenvatinib. The study found for the first time that USP22 and JMJD8 are upregulated in Lenvatinib resistant HCC cells. In addition, the expression level of stemness related proteins (CD133, C-MYC, BMI1, β-CATENIN) in drug-resistant cells was higher than that in wild-type HCC cells. Knockdown of USP22 in drug-resistant HCC cells could reduce the invasion, migration and stemness of cells. Next, we explored the mechanism of USP22 in Lenvatinib resistance of HCC cells. Under the treatment of Lenvatinib, USP22 knockdown inhibited the cell viability of drug-resistant HCC cells and promoted the apoptosis of drug-resistant cells. Animal experiments in nude mice further demonstrated the important role of USP22 in inducing the resistance of HCC to Lenvatinib in vivo. More importantly, we found that USP22 and JMJD8 constitute a functional axis regulating the drug resistance of Lenvatinib in HCC. In the rescue experiment, the overexpression of JMJD8 could reduce the apoptosis induced by USP22 knockdown. In general, this study shows that USP22-JMJD8 is a drug design target for the mechanism of Lenvatinib resistance in HCC, which may improve the long-term efficacy of Lenvatinib.