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A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
Screening for PPAR Responsive Regulatory Modules in Cancer
Merja Heinäniemi1, Carsten Carlberg
1Life Sciences Research Unit, University of Luxembourg, 1511 Luxembourg, Luxembourg.
Abstract:
Peroxisome proliferator-activated receptors (PPARs) have via their large set of target genes a critical impact on numerous diseases including cancer. Cancer development involves numerous regulatory cascades that drive the progression of the malignancy of the cells. On a genomic level, these pathways converge on regulatory modules, some of which contain colocalizing PPAR binding sites (PPREs). We developed an in silico screening method that incorporates experiment- and informatics-derived evidence for a more reliable prediction of PPREs and PPAR target genes. This method is based on DNA-binding data of PPAR subtypes to a panel of DR1-type PPREs and tracking the enrichment of binding sites from multiple species. The ability of PPARgamma to induce cellular differentiation and the existence of FDA-approved PPARgamma agonists encourage the exploration of possibilities to activate or inactivate PPRE containing modules to arrest cancer progression. Recent advances in genomic techniques combined with computational analysis of binding modules are discussed in the review with the example of our recent screen for PPREs on human chromosome 19.
Insights
Peroxisome proliferator-activated receptors (PPARs) regulate genes impacting cancer. A new in silico method reliably predicts PPAR binding sites (PPREs) and target genes, aiding cancer therapy development.
Area of Science:
- Genomics and Molecular Biology
- Computational Biology
- Cancer Research
Background:
- Peroxisome proliferator-activated receptors (PPARs) significantly influence diseases, including cancer, through their extensive target genes.
- Cancer progression involves complex regulatory cascades converging on genomic regulatory modules, some containing PPAR binding sites (PPREs).
Purpose of the Study:
- To develop a robust in silico screening method for accurately predicting PPREs and PPAR target genes.
- To explore the therapeutic potential of targeting PPRE-containing modules for cancer treatment.
Main Methods:
- Developed an in silico screening approach integrating experimental and informatics data.
- Utilized DNA-binding data of PPAR subtypes to DR1-type PPREs.
- Incorporated cross-species enrichment analysis of binding sites.
Main Results:
- The developed method provides a more reliable prediction of PPREs and their associated PPAR target genes.
- Demonstrated the application of the method in screening for PPREs on human chromosome 19.
Conclusions:
- The computational method enhances the identification of functional PPREs and PPAR target genes.
- Activating or inactivating PPRE modules holds promise for arresting cancer progression, particularly given PPARgamma's role in differentiation and existing drug approvals.
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