PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ–DNMT1 Interactions in the Genome

Abstract

Background: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. Methods: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). Results: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ–DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein–protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. Conclusions: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.

Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma

“…Recently, Pazienza et al demonstrated that PPARγ and DNMT1 are equally expressed in human pancreatic cancer cell lines, suggesting their importance in cancer genesis [ 42 ]. For their part, Ceccarelli et al proposed that the activation of PPARγ by eicosatetraenoic acid improves the interaction with DNMT1 and HDAC1 in the CpG islands of the Hic-1 gene [ 43 ], while Sharma A et al, examined the PPARγ-DNMT1 interaction through PPAR-binding elements (PPRE) in an in silico model [ 44 ]. Our molecular docking analyses suggest that PFD acts as an agonist ligand of PPARγ-LBD, facilitating the formation of complexes with the BAH1 domain of DNMT1 (ΔG −23.48 kcal/mol), enhancing its methyltransferase activity.…”

Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma

“…Furthermore, Sharma A et al evaluated in an in-silico model the potential role of PPARγ-DNMT1 interaction via PPAR-binding elements (PPRE) [43]. This evidence indicates that is possible that PFD activates PPARγ facilitating the formation of complexes with BAH1 domain of DNMT1, thus increasing the activity of this enzyme.…”