Abstract
Adenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P < 0.0001) and normal tissues (P = 0.0015). Although the difference in mRNA expression was not statistically significant in all of them, the selected 49 cases of CRC tissues with AK5 hypermethylation with the cut off value of 40% showed a significant inverse correlation with mRNA expression (P = 0.0003). DNA methylation of AK5 promoter significantly decreased and AK5 expression recovered by 5-aza-2′-deoxycytidine, DNA methyltransferase inhibitor in CRC cell lines. In addition, AK5 promoter activity significantly decreased due to DNA methyltransferase, and it increased due to 5-aza. Moreover, AK5 regulated the phosphorylated AMPK and mTOR phosphorylation and inhibited the cell migration and cell invasion in CRC cell lines. Furthermore, low AK5 expression is associated with poor differentiation (P = 0.014). These results demonstrate that the AK5 promoter is frequently hypermethylated and induced methylation-mediated gene down-regulation. AK5 expression regulates AMPK/mTOR signalling and may be closely related to metastasis in colorectal adenocarcinoma.
Highlights
The causes of colorectal cancer (CRC) are heterogeneous and include multistep tumorigenesis caused by genetic and epigenetic v ariations[1,2]
Adenylate kinase 5 (AK5) was significantly hypermethylated in CRC tissues compared to adjacent normal tissue (P < 0.0001), and it was hypermethylated in adjacent normal tissues compared to normal tissues (P = 0.0004, Fig. 1b)
AK5 mRNA expression in normal tissues gradually decreased in adjacent normal tissues and CRC tissues, but the change was not significant (Fig. 1c)
Summary
The causes of colorectal cancer (CRC) are heterogeneous and include multistep tumorigenesis caused by genetic and epigenetic v ariations[1,2]. Previous studies showed that CDH1, P16, hMLH1, and various tumour suppression genes involved in several signal pathways are inactivated by DNA hypermethylation during colorectal tumorigenesis[7,8]. Various panels of CRC-specific DNA hypermethylation genes were named CpG island methylator phenotype (CIMP)[9]. These CIMP markers were used to constitute factors for the development and prognosis of the serrated pathway in CRC and were used to investigate this pathway via clinical trials[10]. Adenylate kinase (AK) is known to have three domains consisting of a core domain, AMP binding domain (AMPbd), and a Lid domain (LID)[12] It can exist in any cell in the organism, and it plays an important role in cell energy metabolisms and nucleotide. AK5 expression in CRC tissue was analysed for correlation with various clinicopathological characteristics
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