Abstract
Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is a critical global health concern
Ubiquitin-conjugating enzyme E2S (UBE2S) upregulation is positively related to poor prognosis of HCC patients To identify a novel ubiquitination-related driver gene for HCC, we analyzed the transcriptome profiling for HCC and non
Tumoral liver tissues in TCGA database and screened for differentially expressed genes (DEGs) from KEGG gene sets involved in ubiquitin-mediated proteolysis (KEGG UBIQUITIN MEDIATED PROTEOLYSIS) in these tissues based on the criteria of false discovery rate (FDR) < 0.05 and fold change ≥2
Summary
Hepatocellular carcinoma (HCC) is a critical global health concern. Approximate 79 million new cases and 75 million HCC-related deaths annually occur worldwide [1, 2]. Based on the RNA sequencing for FOXM1knockdown HCC cells, we found that FOXM1 knockdown in HCC cells suppressed UBE2S mRNA level, FOXM1 pathway, AKT phosphorylation pathway, protein ubiquitination regulation as well as the drug response pathways (Fig. 3N–Q).
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