Jianxin Li , Yu Zheng , Chaojiang Chen , Zhuoyuan Lin , Jiangang Pan , Funeng Jiang , Weide Zhong
{"title":"WTAP-mediated m6A modification of ARG2 mRNA Inhibits Its expression and drives prostate cancer malignant progression","authors":"Jianxin Li , Yu Zheng , Chaojiang Chen , Zhuoyuan Lin , Jiangang Pan , Funeng Jiang , Weide Zhong","doi":"10.1016/j.mrfmmm.2025.111912","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) incidence increases as age advances and seriously endangers men’s health worldwide. Arginase 2 (ARG2) has been identified as a potential diagnostic and prognostic marker for PCa. However, the molecular mechanisms underlying its function in PCa remain undefined.</div></div><div><h3>Methods</h3><div>ARG2 mRNA and protein expression were quantified in PCa tissues and cells using qRT-PCR and Western blot. Cellular proliferation, glucose consumption, lactate production, apoptosis, and ferroptosis were evaluated via EdU incorporation, colony formation assays, commercial kits, and flow cytometry. Subsequently, the xenograft model was established to assess ARG2’s role in tumor growth <em>in vivo</em>. Bioinformatics analysis and RNA immunoprecipitation (RIP) were employed to investigate the interaction between Wilms’ tumor 1-associating protein (WTAP), a key component of the N6-methyladenosine (m6A) methyltransferase complex, and ARG2 mRNA. Besides, mRNA stability was determined using actinomycin D chase assays.</div></div><div><h3>Results</h3><div>ARG2 exhibited low expression in PCa tissues and cells. Upregulation of ARG2 inhibited proliferation and glycolysis, and promoted apoptosis, oxidative stress and ferroptosis of PCa cells. However, silencing ARG2 had the opposite effects. I<em>n vivo</em>, ARG2 overexpression suppressed tumor growth. Mechanistically, WTAP bound directly to ARG2 mRNA, and their expression levels were inversely correlated. WTAP knockdown phenocopied ARG2 overexpression by repressing proliferation and glycolysis and enhancing apoptosis/ferroptosis, effects reversed by ARG2 silencing. ARG2 overexpression counteracted the oncogenic effects of WTAP overexpression.</div></div><div><h3>Conclusion</h3><div>WTAP bound to ARG2 and suppressed its expression, thereby promoting the malignant progression of PCa.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111912"},"PeriodicalIF":1.9000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0027510725000156","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Prostate cancer (PCa) incidence increases as age advances and seriously endangers men’s health worldwide. Arginase 2 (ARG2) has been identified as a potential diagnostic and prognostic marker for PCa. However, the molecular mechanisms underlying its function in PCa remain undefined.
Methods
ARG2 mRNA and protein expression were quantified in PCa tissues and cells using qRT-PCR and Western blot. Cellular proliferation, glucose consumption, lactate production, apoptosis, and ferroptosis were evaluated via EdU incorporation, colony formation assays, commercial kits, and flow cytometry. Subsequently, the xenograft model was established to assess ARG2’s role in tumor growth in vivo. Bioinformatics analysis and RNA immunoprecipitation (RIP) were employed to investigate the interaction between Wilms’ tumor 1-associating protein (WTAP), a key component of the N6-methyladenosine (m6A) methyltransferase complex, and ARG2 mRNA. Besides, mRNA stability was determined using actinomycin D chase assays.
Results
ARG2 exhibited low expression in PCa tissues and cells. Upregulation of ARG2 inhibited proliferation and glycolysis, and promoted apoptosis, oxidative stress and ferroptosis of PCa cells. However, silencing ARG2 had the opposite effects. In vivo, ARG2 overexpression suppressed tumor growth. Mechanistically, WTAP bound directly to ARG2 mRNA, and their expression levels were inversely correlated. WTAP knockdown phenocopied ARG2 overexpression by repressing proliferation and glycolysis and enhancing apoptosis/ferroptosis, effects reversed by ARG2 silencing. ARG2 overexpression counteracted the oncogenic effects of WTAP overexpression.
Conclusion
WTAP bound to ARG2 and suppressed its expression, thereby promoting the malignant progression of PCa.
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.