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      Glycolysis and tumor progression promoted by the m6A writer VIRMA via m6A-dependent upregulation of STRA6 in pancreatic ductal adenocarcinoma.

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          Abstract

          Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, highlighting the urgent need to elucidate the underlying oncogenic mechanisms. VIRMA is a classic isoform of methyltransferases that participates in epigenetic transcriptomic modification in eukaryotic mRNAs. However, the exact roles of VIRMA in PDAC remain unclear. Here, we identified that VIRMA is highly expressed in PDAC, and histone modifications of the promoter may partly account for this dysregulation. Moreover, VIRMA is closely related to glycolysis and poor prognosis in PDAC. We further determined that STRA6 is a direct downstream target of VIRMA in PDAC by RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq). VIRMA is involved in gene expression regulation via 3' UTR targeting of STRA6 mRNA. Furthermore, the m6A reader IGF2BP2 was shown to critically contribute to the stability of STRA6 mRNA. We describe the role of VIRMA in promoting signaling via the STRA6/STAT3 axis, which results in increased levels of HIF-1α, a key activator of glycolysis. In vivo and in vitro experiments reveal that the VIRMA-STRA6-STAT3-HIF-1α axis plays an instrumental role in glycolysis and tumor progression in PDAC. In conclusion, we demonstrate that VIRMA can increase glycolysis in PDAC by upregulating STRA6, a cell surface membrane protein that stimulates the STAT3 pathway, thereby activating HIF-1α and leading to pancreatic cancer malignancy. Overall, our data strongly suggest that the VIRMA-STRA6-STAT3-HIF-1α axis is a viable therapeutic target in PDAC.

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          Author and article information

          Journal
          Cancer Lett
          Cancer letters
          Elsevier BV
          1872-7980
          0304-3835
          May 28 2024
          : 590
          Affiliations
          [1 ] Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China.
          [2 ] Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China.
          [3 ] Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. Guangdong, PR China.
          [4 ] Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China. Electronic address: yind3@mail.sysu.edu.cn.
          [5 ] Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China. Electronic address: huangkh@mail.sysu.edu.cn.
          [6 ] Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China. Electronic address: liyq255@mail.sysu.edu.cn.
          Article
          S0304-3835(24)00233-7
          10.1016/j.canlet.2024.216840
          38604311
          b51a8238-097b-4447-9558-ac8242a32152
          History

          VIRMA,m(6)A modification,Glycolysis,PDAC,STRA6
          VIRMA, m(6)A modification, Glycolysis, PDAC, STRA6

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