FTO blocks RNA translational activity via the loss of N6-methyladenosine methylation at 5' UTR regulated by RBM5 in cisplatin-resistant NSCLC

J Cell Physiol. 2024 Aug;239(8):e31296. doi: 10.1002/jcp.31296. Epub 2024 May 14.

Abstract

N6-methyladenosine (m6A) methylation has been widely regarded in numerous biological functions including CR. Nonetheless, the molecular process of m6A methylation behind CR in non-small cell lung cancer (NSCLC) has no apparent significance. We identified in this study that the expression of FTO alpha-ketoglutarate dependent dioxygenase (FTO) was downregulated in CR NSCLC tissues and cells in vivo and in vitro. Additionally, RIP-seq indicated that loss of FTO contributed to the elevated m6A methylation at 5'-untranslated region of RNAs which were closely connected with tumor resistance and malignancy, and FTO exerted to exclude the recruitment of eIF3A to these target genes in CR NSCLC. Moreover, FTO-enriched transcripts displayed a reduced translational capability in CR NSCLC compared to the regular NSCLC cells. Finally, we also identified RNA binding motif protein 5 (RBM5) that could specially interact with FTO in regular NSCLC compared to CR NSCLC. Deficiency of RBM5 resulted in the abnormal recognition of transcripts by FTO, and led to the translation silencing of genes associated with CR such as ATP7A, ERCC1, CD99, CDKN3, XRCC5, and NOL3. Taken together, our data characterized FTO as a novel translation regulator and revealed the molecular mechanism on gene translation through the synergistic effects with RBM5 and m6A methylation in CR NSCLC cells.

Keywords: FTO; N6‐methyladenosine methylation; cisplatin resistance; gene translation; non‐small cell lung cancer.

MeSH terms

  • 5' Untranslated Regions* / genetics
  • A549 Cells
  • Adenosine* / analogs & derivatives
  • Adenosine* / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / genetics
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO* / metabolism
  • Animals
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cisplatin* / pharmacology
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic* / genetics
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Methylation
  • Protein Biosynthesis / genetics
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Tumor Suppressor Proteins

Substances

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Adenosine
  • FTO protein, human
  • N-methyladenosine
  • RNA-Binding Proteins
  • Cisplatin
  • 5' Untranslated Regions
  • RBM5 protein, human
  • DNA-Binding Proteins
  • Cell Cycle Proteins
  • Tumor Suppressor Proteins