PPARγ disease gene network and identification of therapeutic targets for prostate cancer

Abstract

Peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear hormone receptor superfamily. Recently published reports demonstrate the importance of a direct repeat 2 (DR2) as a PPARγ-responsive element in addition to the canonical direct repeat 1 (DR1) Peroxisome proliferator response elements (PPREs). However, a comprehensive and systematic approach to constructing de novo disease-specific gene networks for PPARγ is lacking, especially one that includes PPARγ target genes containing either DR1 or DR2 site within their promoter region. Here, we computationally identified 1154 PPARγ direct target genes and constructed the PPARγ disease gene network, which revealed 138 PPARγ target genes that are associated with 65 unique diseases. The network shows that PPARγ target genes are highly associated with cancer and neurological diseases. Thirty-eight PPARγ direct target genes were found to be involved in prostate cancer and two key (hub) PPARγ direct target genes, PRKCZ and PGK1, were experimentally validated to be repressed upon PPARγ activation by its natural ligand, 15d-PGJ₂ in three prostrate cancer cell lines. We proposed that PRKCZ and PGK1 could be novel therapeutic targets for prostate cancer. These investigations would not only aid in understanding the molecular mechanisms by which PPARγ regulates disease targets but would also lead to the identification of novel PPARγ gene targets.

Keywords::

• PPARγ disease gene network
• direct repeat 2
• PPARγ target genes in prostate cancer
• genome-wide DR1 and DR2 PPARγ genes
• PPARγ protein–protein network

Percentage of genes in each disease group for 718 genes with PPRE sites; 718 genes with/without PPRE sites selected at random from the human genome and 718 genes with no PPRE sites selected at random from the human genome. It is clearly seen that genes with PPRE sites are more likely to be involved in cancer and neurological disorders.

List of 1154 genes of which 748 DR1 genes and 406 DR 2 genes and 118 DR1 and DR2 genes with PPRE sites in the 5kb promoter region were obtained using the PPRESearch prediction (Supplementary 1a).

Many transcripts have same gene symbol and same PPRE sites hence they are grouped together under one gene name. 718 genes (with gene names) were finalized and used for further analysis. A list of PPAR? DR1 and DR2 target genes from these 718 genes are shown in the Supplementary 1b.

The PPRE sites present in 5′ promoter region of the genes and DR1/DR2 column indicates the type of directed repeat present in each gene. Supplementary file 2 provides the complete names for these gene symbols.