ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades

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.