Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Intratumour heterogeneity in gene expression, particularly in cancer stem cells (CSCs), limits the efficacy of single-gene targeted therapies.
• Long mononucleotide A-T repeats act as cis-regulatory elements, influencing the expression of multiple genes in cancers like lung cancer.
• Targeting these A-T repeats presents a potential strategy to broadly disrupt cancer-driving gene networks.

Purpose of the Study:

• To investigate the role of A-T repeats in regulating gene expression in lung cancer and CSCs.
• To evaluate the therapeutic potential of a peptide nucleic acid (PNA) oligo, PNA-A15, designed to disrupt A-T repeat transcriptional control.

Main Methods:

• Separation of CSCs from parental lung cancer cell lines.
• Analysis of A-T repeat counts in differentially regulated genes between CSCs and parental cells.
• Assessment of PNA-A15 toxicity and effects on CSC phenotypes in normal and cancer cells.
• Genome-wide expression analysis to identify PNA-A15-dysregulated genes in CSCs.

Main Results:

• A difference in A-T repeat numbers was observed in genes differentially regulated between CSCs and parental cells.
• PNA-A15 demonstrated toxicity towards lung cancer cells and CSCs, while sparing non-cancerous cells.
• PNA-A15 effectively dysregulated multiple genes within lung CSCs.

Conclusions:

• PNA-A15 represents a novel therapeutic agent with the potential to target the transcriptional control of numerous genes in lung CSCs.
• This approach offers a promising strategy for overcoming therapeutic resistance driven by gene expression heterogeneity.