The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression

Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade beta -catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated beta -catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/beta -catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.

Automated summary

Recent evidence has shown the significant role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in hepatocellular carcinoma (HCC) patients. A study identified UBE2T as a key gene in HCC, revealing its involvement in regulating liver CSCs, and suggesting it as a potential therapeutic target for HCC. The study also uncovered a novel UBE2T/Mule/beta-catenin signaling cascade that plays a critical role in the regulation of liver CSCs, highlighting its importance in HCC treatment.