A multi-omics exploration of PPARG activation in colon cancer: kinases featuring a PPRE sequence within regulatory...

As members of the nuclear receptor (NR) family of transcription factors, peroxisome proliferator-activated receptors (PPARs) regulate essential cellular processes, including lipid metabolism, glucose uptake, cell proliferation, and programmed cell death through ligand-mediated activation. Within the PPAR subfamilies, PPAR-γ (PPARG) is crucial to the development of fat cells, sensitivity to insulin, apoptosis, and metastasis. Furthermore, it demonstrates properties that counteract fibrosis and inflammation, thus establishing itself as a notable target for therapeutic interventions against conditions such as type 2 diabetes and cancer. PPARG is reported to be a promising target for patients diagnosed with colorectal cancer (CRC). Globally, colorectal cancer ranks as the third most prevalent malignancy and is responsible for approximately 10% of all cancer mortalities, and PPARG is significantly expressed in 70% of the sporadic CRC. In individuals with CRC, the precise function of PPARG remains not entirely comprehended and elucidation of the PPARG transcriptional regulation in CRC seems promising.

This study integrates RNA-seq and ChIP-seq reads to analyze the effects of Rosiglitazone on HT-29 colon cancer cells. Peak calling analysis from ChIP-seq data identified 14,000 to 34,000 binding sites for PPARG across different experimental conditions. RNA-seq analysis highlighted significant differential gene expression in Rosiglitazone-treated cells, with 4362 and 6780 genes significantly regulated at 24 and 48 h, respectively. The correlation of these datasets with PPRE-associated kinases resulted in the identification of 18 differentially expressed genes (DEGs), followed by subsequent analysis of gene ontology, pathway enrichment, and protein-protein interactions, culminating in the elucidation of seven hub genes (PTK2, HGS, CDK8, PRPF6, PRKDC, PRKCZ, MET). Further these hub genes correlated with CRC progression and patient survival. Validation using independent GEO datasets (GSE113513 and GSE210693) and gene effect scores derived from CRISPR knockout screens further supported the functional impact of these hub genes. Disease ontology and mutational analyses implicated the hub genes in various cancers, including CRC. Moreover, miRNA analysis identified 37 experimentally validated miRNAs potentially modulating hub gene expression.

These findings advance our understanding of PPARG's regulatory network and underscore its potential as a therapeutic target, establishing a robust framework for future research in PPARG-related pathways.