Impairment of DYRK2 by DNMT1-mediated transcription augments carcinogenesis in human colorectal cancer

Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a protein kinase that functions as a novel tumor suppressor. Previous studies have reported that DYRK2 expression is decreased in colorectal cancer compared with adjacent non-tumor tissues. However, the regulatory mechanisms by which the expression of DYRK2 is diminished remain unknown. The aim of the present study was to determine the regulatory mechanisms of DYRK2 expression. The present study identified the promoter regions of the DYRK2 gene and demonstrated that they contained CpG islands in human cancer cells. In addition, the DYRK2 promoter region exhibited a higher level of methylation in colorectal cancer tissues compared with healthy tissues from clinical samples. DYRK2 expression was increased at the mRNA and protein level in colorectal cancer cell lines by treatment with 5-Azacytidine, a demethylating agent. The results further demonstrated that knockdown of DNA methyltransferase (DNMT) 1 elevated DYRK2 expression in colorectal cancer cell lines. A colitis-related mouse carcinogenesis model also exhibited a lower DYRK2 level in colorectal cancer tissues compared with adjacent non-tumor tissues. In this model, nuclear staining of DNMT1 was detected in colorectal cancer cells, whereas a cytoplastic distribution pattern of DNMT1 staining was exhibited in healthy tissue. Overall, these findings suggested that DYRK2 expression was downregulated via transcriptional regulation by DNMT1 to elevate the proliferation of colorectal cancer cells.