ENPP2 Methylation in Health and Cancer.

Maria Panagopoulou,Ekaterini Chatzaki,Dionysios Fanidis,Vassilis Aidinis

doi:10.3390/ijms222111958

Abstract

Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico the methylation of ENPP2 analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected p-value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased ENPP2 mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of ENPP2 in health and cancer and points out specific DMCs of value as prognostic biomarkers.

Highlights

ATX encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a secreted lysophospholipase D and belongs to the ENPP (1–7) protein family [1]
ENPP2 promoter cancer these findings show that Differentially Methylated CpGs (DMCs) identified in the ENPP2 promoter in cancer are in found in are found in sites for and Transcription Factor (TF) binding, and altered methylation is likely to sites significant forsignificant altered methylation is likely to affect tranaffect transcription and expression scription and expression of ATX. of ATX
Eight DMCs were identified between cancer and control tissues (3 in the Transcription Start Site (TSS), 1 in the 1st exon, 4 in the gene body) and 6 of them were common to those found in the GSE76938 dataset

Summary

Introduction

ATX encoded by ENPP2 is a secreted lysophospholipase D (lysoPLD) and belongs to the ENPP (1–7) protein family [1]. ATX is responsible for the synthesis of the majority of extracellular LPA in blood. LPA acts locally upon increased ATX levels through at least six G protein-coupled receptors [2]. Increased ATX activity and levels have been correlated with several inflammatory [3] and fibroproliferative conditions [4], as well as with cancer [5]. Increased expression of ATX in blood and the subsequent increase of LPA have been correlated with cancer invasiveness [6]. It has been shown that ATX expression is upregulated in cancerous [7,8] and fibrotic tissues [9]

Methods

Results

Conclusion