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-PGJ(2) 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.

Benefits of curcumin in brain disorders

“…PPAR‐γ directly or indirectly influences the expression of genes (TFAM, NRF1, NRF2, Bax, and Bcl‐2) that are involved in neurodegeneration. Activation of NF‐κB pathway triggers inflammation by mediating the release of proinflammatory factors like IL‐1, IL‐6, MAP‐1, CCL5, COX‐2, iNOS, MMP‐9, and TNF . This inflammation leads to progressive loss of the neuronal matter and results in the aggravation of neurological diseases like stroke, AD, PD, HD, and MS .…”

“…Activation of NF-κB pathway triggers inflammation by mediating the release of proinflammatory factors like IL-1, IL-6, MAP-1, CCL5, COX-2, iNOS, MMP-9, and TNF. 136,137 This inflammation leads to progressive loss of the neuronal matter and results in the aggravation of neurological diseases like stroke, AD, PD, HD, and MS. 136 Curcumin has been reported to up-regulate PPAR-γ. This has been reported to suppress the inflammatory NF-κB pathway.…”

Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

“…We have recently shown that PKM2 is downregulated by PPAR γ activation by 15d-PGJ 2 , a PPAR-gamma ligand [53]. Concurrently, PGK1, another important enzyme at ATP generation step in glycolysis, has been reported by us to be downregulated by PPAR gamma upon activation by 15d-PGJ 2 [54]. …”

Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer

“…PPARs function as transactivation factors that heterodimerize with retinoid X receptors (RXRs) upon activation and bind to specific response elements (PPREs) in the target DNA of various target genes [7–10]. PPRE consists of direct repeat (DR) hexameric sequences (AGGTCA), separated by one or two nucleotides (DR-1 and DR-2 element) [11]. Distinct areas such as the DNA binding and the ligand-binding transactivation domains have been identified, and these domains influence the transduction of the PPAR-induced response.…”

“…In addition, loss-of-function mutations of PPAR γ have been found in some human colon and thyroid carcinomas [13]. In vitro and in vivo studies have demonstrated antiproliferative and proapoptotic actions of PPAR γ agonists such as 15d-PGJ 2 and thiazolidinediones (TZDs) thus suggesting that PPAR γ could be a promising therapeutical target for the treatment of cancer [11, 14]. Binding of agonist ligands to PPAR γ triggers a conformational change that attracts transcriptional coactivators, including members of the steroid receptor coactivator (SRC) family [5, 15].…”