ENPP2 Methylation in Health and Cancer

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.

ENPP2 Promoter Methylation Correlates with Decreased Gene Expression in Breast Cancer: Implementation as a Liquid Biopsy Biomarker

“…Indeed, expression analysis showed decreased transcription in BrCa in relation to normal tissues, and increased methylation of all PA CGs was reversely correlated to mRNA expression, results also confirmed by analysis in the UALCAN platform. These results agree with our previous findings in HCC, melanoma, CRC, LC, and PC, showing ENPP2 hypermethylation in PA and decreased expression [ 18 ].…”

“…ATX’s encoding gene ENPP2 , is epigenetically regulated, as aberrant methylation patterns were described in five different cancer types and were correlated to mRNA expression. Furthermore, increased methylation of ENPP2 was connected to poor prognostic parameters [ 18 ]. In most cancer types, ATX is increased, but BrCa cells express little ATX.…”

“…Unfortunately, expression data from metastatic samples were not available to allow correlation with methylation and deeper understanding in the process of metastasis. It has to be noted that in our previous work, ENPP2 hypermethylation in lung cancer was correlated with advanced cancer stage [ 18 ].…”

“…By employing an in silico approach, we have recently described ENPP2 methylation profiles in health and malignancy, showing that methylation is an active level of ATX expression regulation in cancer. Increased methylation of promoter and first exon cytosine-guanine dinucleotides(CGs) and respective decreased ENPP2 mRNA expression were found in prostate and lung cancers and were correlated to poor prognostic parameters [ 18 ].…”

Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?

“…Autotaxin (ATX) is a member of the ecto-nucleotidase family of enzymes encoded by the ENPP2 gene [ 48 ]. It was initially isolated from melanoma cell lines and was identified as a motility factor [ 49 ].…”