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Published on: July 3, 2013
Ion-Channel-Mediated Drug Repurposing Opportunities Validated by Single-Cell Perturbation in Colorectal Cancer
Zhongyuan Dong1, Xuanlin Meng1, Lianghua Wang1,2
1Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China.
Abstract:
Colorectal cancer (CRC) remains a leading cause of cancer mortality, yet no systematic effort has linked druggable CRC driver genes to downstream ion channel effectors. We integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network pharmacology to identify CRC hub genes and their ion channel connections, validated by dual single-cell perturbation approaches: variational graph autoencoder-based virtual knockout (VGAE-KO) and experimental HCT116 CRISPRi Perturb-seq (6 genes, 8445 cells). WGCNA identified 100 hub genes spanning three functional programs. Ribosomal proteins link to K+ channels (RPS21 → KCNQ2, targetable by EMA-approved ataluren, passed dual validation at 97.8th-98.7th percentile). RNA processing genes connect to Cl- channels (LSM7 → CLIC1, strongest signal at 99.8th-99.4th percentile). Immune checkpoint receptors (LAG3, CD27) connect via PPI intermediates to Ca2+ and K+ channels, targetable by relatlimab (FDA-approved) and varlilumab (Phase 2). This work maps previously unknown links between CRC driver genes and ion channel regulation, with the ataluren-RPS21-KCNQ2 axis ready for pharmacological testing.
Insights
This study identifies novel connections between colorectal cancer (CRC) driver genes and ion channels. A key finding is the ataluren-RPS21-KCNQ2 axis, offering a new therapeutic avenue for CRC.
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.
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