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ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades

Andrea Pérez-González1, Ivonne Ramírez-Díaz1,2, Josué Guzmán-Linares1

  • 1International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Instituto de Ciencias, Ecocampus, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla 72570, Mexico.

Cancers
|February 24, 2024
PubMed

Insights

The neddylation inhibitor MLN4924 reverses stemness and epithelial-mesenchymal transition in lung cancer cells. This finding offers potential for new lung cancer therapies by restoring chemosensitivity and promoting differentiation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Bioinformatics

Background:

  • Lung adenocarcinoma (LUAD) exhibits resistance to targeted therapies like gefitinib.
  • Cancer stemness and epithelial-mesenchymal transition (EMT) are key drivers of drug resistance and tumor progression.
  • Neddylation is a post-translational modification implicated in regulating protein stability and function in cancer.

Purpose of the Study:

  • To investigate the transcriptomic effects of the neddylation inhibitor MLN4924 on lung adenocarcinoma cells.
  • To explore the relationship between ncRNA expression, stemness factors, and drug resistance in LUAD.
  • To determine if MLN4924 can reverse stemness and EMT phenotypes in gefitinib-resistant LUAD cells.

Main Methods:

  • Integrative transcriptomic in silico analysis of A549 and PC9GR cell lines.
  • Treatment with the neddylation inhibitor MLN4924.
  • Differential gene expression analysis focusing on ncRNAs and stemness factors.
  • Pathway enrichment analysis of differentially expressed genes.

Main Results:

  • MLN4924 treatment upregulated pro-carcinogenic and differentiation pathways while downregulating stemness and survival pathways in A549 cells; PC9GR cells showed inverse effects.
  • Upregulated ncRNAs upon MLN4924 treatment inversely correlated with stemness factor expression.
  • MLN4924 abrogated stemness (KLF4, FGFR2) and EMT (ZEB2, TWIST2, SNAI2, CDH2, VIM) factors in PC9GR cells.
  • Upregulated ncRNAs targeted mRNAs enriched in proliferation, differentiation, and apoptosis pathways.
  • Downregulated ncRNAs targeted mRNAs implicated in stem cell maintenance.

Conclusions:

  • Neddylation inhibition by MLN4924 can reverse stemness and EMT phenotypes in lung cancer cells.
  • MLN4924 promotes epithelial differentiation pathways, potentially offering a protective role in lung cancer.
  • Targeting neddylation presents a promising strategy to enhance chemosensitivity and combat lung tumorigenesis.
Keywords:
chemosensitivityepigenetic modulationlung adenocarcinomancRNAneddylationstemness

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