Ion-Channel-Mediated Drug Repurposing Opportunities Validated by Single-Cell Perturbation in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• Colorectal cancer (CRC) is a major cause of cancer death.
• No prior research systematically linked CRC driver genes to ion channel regulation.

Purpose of the Study:

• To identify druggable colorectal cancer (CRC) driver genes and their downstream ion channel targets.
• To validate these gene-ion channel connections using computational and experimental methods.

Main Methods:

• Integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network pharmacology.
• Validated findings using variational graph autoencoder-based virtual knockout (VGAE-KO) and CRISPRi Perturb-seq single-cell experiments.
• Analyzed 8445 cells across 6 genes.

Main Results:

• Identified 100 CRC hub genes linked to three functional programs.
• Discovered a link between ribosomal protein RPS21 and K+ channels (KCNQ2), targetable by ataluren.
• Found connections between RNA processing genes (LSM7) and Cl- channels (CLIC1).
• Linked immune checkpoint receptors (LAG3, CD27) to Ca2+ and K+ channels, targetable by approved or investigational drugs.

Conclusions:

• This research maps previously unrecognized relationships between CRC driver genes and ion channel regulation.
• The ataluren-RPS21-KCNQ2 pathway is a promising candidate for further pharmacological investigation in colorectal cancer.