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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in
Junyi Li1, Tao Pan2, Liuxin Chen1
1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
Abstract:
Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.
Insights
Alternative splicing (AS) alterations are common in cancer, impacting disease severity. This study identifies RNA binding protein (RBP) regulators as potential therapeutic targets for cancer treatment.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- Alternative splicing (AS) is crucial for gene regulation, with its dysregulation frequently observed in various cancers.
- RNA binding proteins (RBPs) are key regulators of AS, and their network perturbations are linked to cancer development.
Purpose of the Study:
- To systematically analyze AS event perturbations across 18 cancer types.
- To identify conserved RNA binding protein (RBP) regulators involved in cancer hallmark pathways.
- To explore the therapeutic potential of targeting RBPs in cancer treatment.
Main Methods:
- Performed a pan-cancer analysis of alternative splicing (AS) events.
- Developed a computational pipeline to identify RNA binding protein (RBP) regulators.
- Analyzed RBP expression for cancer subtyping and identified potential small molecule drug targets.
Main Results:
- AS alterations are prevalent in cancer and associated with disease severity.
- Identified conserved RBP regulators crucial for AS of cancer hallmark genes.
- Discovered that RBP expression aids in cancer subtyping, revealing four distinct kidney cancer subtypes with prognostic differences.
Conclusions:
- RNA binding proteins (RBPs) are significant therapeutic targets in cancer.
- Comprehensive AS perturbation analysis offers novel insights into RBP regulatory functions in oncogenesis.
- Identified potential small molecules for targeting RBPs, suggesting new avenues for cancer therapy.
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