New findings suggest USP22 as a promising target for the HCC therapy

Recently, the research team led by Prof. XU Xiao from the Zhejiang University School of Medicine published a research paper entitled “SP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation” in the journal of Gut.

In this study, researchers established cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes to detect the stemness of HCC cells. They applied immunoprecipitation, ubiquitination assay and chromatin immunoprecipitation to explain the mutual regulation mechanism of USP22 and HIF1α and demonstrated the clinical significance by means of HCC patient samples and The Cancer Genome Atlas data. The in vivo USP22-targeting experiment was also performed in mice bearing HCC.

Researchers found out that USP22 promotes hypoxia-induced HCC stemness and glycolysis by deubiquitinating and stabilising HIF1α. As direct target genes of HIF1α, USP22 and TP53 can be transcriptionally regulated by HIF1α under hypoxic conditions. In TP53 wild-type HCC cells, HIF1α induces TP53-mediated inhibition of HIF1α-induced USP22 upregulation while in TP53-mutant HCC cells, USP22 and HIF1α form a positive feedback loop and promote the stemness of HCC. Researchers also reveal that HCC patients with a loss-of-function mutation at TP53 and high USP22 and/or HIF1α expression tend to have a worse prognosis.

Considering the current lack of USP22-specific inhibitors, the team has developed a novel type of ROS-responsive nano-gene drug. The reduced expression of USP22 in tumors can significantly hinder the growth of HCC and enhance the sensitivity of HCC cells to Sorafenib, providing an effective strategy for the HCC therapy.