E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI:10.1016/j.mrfmmm.2025.111902

Di Zhang, Xinwu Zhang, Shuai Chang, Yao Zhao, Li Zhang

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引用次数: 0

Abstract

Background

Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.

Methods

RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis in vivo.

Results

High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. In vivo, USP19 knockdown controlled HCC growth by modulating c-Myc.

Conclusion

E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.