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

Amit Sharma,Panagiotis Katsonis,M Michael Gromiha,Fabian Tobar-Tosse,Anoosha Paruchuri,Martina C Herwig-Carl,Michael Ludwig,Hongde Liu,Athira Menon,Tikam Chand Dakal,Karin U Loeffler,Frank G Holz,Arijit Biswas,Ingo G H Schmidt-Wolf,Olivier Lichtarge

doi:10.3390/cancers13163993

Abstract

Simple SummaryThis study aimed to explore the potential role of PPARγ–DNMT1 interaction through PPAR-responsive elements (PPREs), which we have found to be enriched with Alu repeats. Apart from protein–protein interactions and co-expression in multiple cancer types, we exclusively described a prognostic role for PPARγ in uveal melanoma (UM).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.

Highlights

Studies from the cancer genome suggest that cancer is not merely restricted to certain mutations in genes
The analysis revealed a PPAR-responsive elements (PPREs) and two proximal Alu repeats configured with low complexity and L1 repeats (Alu-Alu-Low complexity-Line/L1) in the vicinity of the identified PPRE
As this motif is strongly conserved in the reverse complement strand, we investigated the distribution of this DNMT1 motif in the phylogenetic hierarchy of the Alu family

Summary

Introduction

Studies from the cancer genome suggest that cancer is not merely restricted to certain mutations in genes (oncogenes, tumor suppressor genes, driver genes). PPARγ is involved in tumorigenesis since it is expressed in different tumors including their microenvironment and promote polarization of anti-inflammatory pro-tumorigenic M2 macrophages [5,6,7,8]. It is still under debate under which conditions pro- or anti-carcinogenic effects dominate (reviewed in [9]). PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer.

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