Glucose-induced LINC01419 reprograms the glycolytic pathway by recruiting YBX1 to enhance PDK1 mRNA stability in hepatocellular carcinoma.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/metabolism ; Liver Neoplasms*/genetics ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/pathology ; Y-Box-Binding Protein 1*/metabolism ; Y-Box-Binding Protein 1*/genetics ; RNA, Long Noncoding*/genetics ; RNA, Long Noncoding*/metabolism ; Glucose*/metabolism; Humans ; Glycolysis/drug effects ; Glycolysis/genetics ; RNA Stability/drug effects ; RNA Stability/genetics ; Animals ; Mice ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics ; Cell Line, Tumor ; Mice, Nude

Metabolic reprogramming provides the necessary energy for the development of malignant tumours and is emerging as a novel tumour treatment strategy. However, the widespread expression of metabolic enzymes in diverse cell types makes the development of specific drugs that target cancer cells without affecting normal cellular functions challenging. Accumulating evidence has demonstrated the essential roles of long non-coding RNAs (lncRNAs) in the regulatory network associated with glucose metabolism in tumour cells. The mechanism and therapeutic potential of cancer-specific lncRNAs in modulating tumour glucose metabolism warrant in-depth exploration. Here we revealed that glucose-induced LINC01419 promoted the growth and metastasis of HCC cells by driving metabolic reprogramming. Mechanistically, LINC01419 directly interacted with Y-box binding protein 1 (YBX1) in the cytoplasm and facilitated its binding to PDK1 mRNA, thus enhancing PDK1 mRNA stability and increasing lactate production. Furthermore, YY1 contributed to the transcriptional activation of LINC01419 in HCC under high-glucose conditions. Notably, administration of an N-acetylgalactosamine (GalNAc)-conjugated siRNA specifically targeting LINC01419 markedly retarded the growth of orthotopic xenograft tumours. These findings provide evidence for an unprecedented regulatory mechanism of LINC01419 involving metabolic reprogramming in human cancer. The newly identified LINC01419/YBX1-PDK1 axis may represent a promising therapeutic target for HCC. Moreover, GalNAc-siLINC01419 holds significant potential for clinical application. KEY POINTS: This study highlights the considerable regulatory role of LINC01419 in the metabolism of HCC. The newly identified LINC01419/YBX1-PDK1 axis constitutes a valuable target. Hepatic-specific delivery of GalNAc-siLINC01419 presents a promising therapeutic strategy for HCC.
(© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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81790252 National Natural Science Foundation of China; 81930123 National Natural Science Foundation of China; 82121004 National Natural Science Foundation of China

Keywords: LINC01419; PDK1; glycolytic pathway; hepatocellular carcinoma; mRNA stability

0 (Y-Box-Binding Protein 1)
0 (YBX1 protein, human)
0 (RNA, Long Noncoding)
IY9XDZ35W2 (Glucose)
0 (PDK1 protein, human)
0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)

Date Created: 20241203 Date Completed: 20241203 Latest Revision: 20241205

20241209

PMC11613097

10.1002/ctm2.70122

39625183