Sprouty4 is epigenetically upregulated in human colorectal cancer

Sprouty4 (SPRY4) has been frequently reported as a tumor suppressor and is therefore downregulated in various cancers. For the first time, we report that SPRY4 is epigenetically upregulated in colorectal cancer (CRC). In this study, we explored DNA methylation and hydroxymethylation levels of <i>SPRY4</i> in CRC cells and patient samples and correlated these findings with mRNA and protein expression levels. Three loci within the promoter region of <i>SPRY4</i> were evaluated for 5mC levels in CRC using the combined bisulfite restriction analysis. In addition, hydroxymethylation levels within <i>SPRY4</i> were measured in CRC patients. Lastly, DNA methylation and mRNA expression data were extracted from CRC patients in multiple high-throughput data repositories like Gene Expression Omnibus and The Cancer Genome Atlas. Combined <i>in vitro</i> and <i>in silico</i> analysis of promoter methylation levels of <i>SPRY4</i> clearly demonstrates that the distal promoter region undergoes hypomethylation in CRC patients and is associated with increased expression. Moreover, a decrease in gene body hydroxymethylation and an increase in gene body methylation within the coding region of <i>SPRY4</i> were found in CRC patients and correlated with increased expression. SPRY4 is epigenetically upregulated in CRC by promoter hypomethylation and hypermethylation within the gene body that warrants future investigation of atypical roles of this established tumor suppressor. SPRY4 gene expression is increased in colorectal cancerThe <i>SPRY4</i> promoter loses DNA methylation, and the gene body gains DNA methylation in colorectal cancerThe gene body of <i>SPRY4</i> loses DNA hydroxymethylation SPRY4 gene expression is increased in colorectal cancer The <i>SPRY4</i> promoter loses DNA methylation, and the gene body gains DNA methylation in colorectal cancer The gene body of <i>SPRY4</i> loses DNA hydroxymethylation