Nucleolin malonylation as a nuclear-cytosol signal exchange mechanism to drive cell proliferation in Hepatocarcinoma by enhancing AKT translation

J Biol Chem. 2024 Oct;300(10):107785. doi: 10.1016/j.jbc.2024.107785. Epub 2024 Sep 19.

Abstract

Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylations are especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, as a novel type of acylations, the involvement of malonylation in cancer remains poorly understood. In this study, we observed a significant reduction in malonyl-CoA levels in hepatocellular carcinoma (HCC), which correlated with a global decrease in malonylation. Subsequent nuclear malonylome analysis unveiled nucleolin (NCL) malonylation, which was notably enhanced in HCC biopsies. we demonstrated that NCL undergoes malonylation at lysine residues 124 and 398. This modification triggers the translocation of NCL from the nucleolus to nucleoplasm and cytoplasm, binding to AKT mRNA, and promoting AKT translation in HCC. Silencing AKT expression markedly attenuated HCC cell proliferation driven by NCL malonylation. These findings collectively highlight nuclear signaling in modulating AKT expression, suggesting NCL malonylation as a novel mechanism through which cancer cells drive cell proliferation.

Keywords: Akt; cell proliferation; hepatocellular carcinoma; malonyl-CoA; malonylation(Kmal); nucleolin.

MeSH terms

  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Cell Nucleus* / metabolism
  • Cell Proliferation*
  • Cytosol / metabolism
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Nucleolin*
  • Phosphoproteins* / genetics
  • Phosphoproteins* / metabolism
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-akt* / genetics
  • Proto-Oncogene Proteins c-akt* / metabolism
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Signal Transduction*

Substances

  • Proto-Oncogene Proteins c-akt
  • Nucleolin
  • Phosphoproteins
  • RNA-Binding Proteins