The role of ADCYAP1, adenylate cyclase activating polypeptide 1, as a methylation biomarker for the early detection of cervical cancer

Abstract

The ADCYAP1 gene encodes an adenylate cyclase activating polypeptide 1. ADCYAP1 has been known to be involved in various biological processes. Multiple cytosine guanine dinucleotides (CpG island) are found in the ADCYAP1 promoter region. Transcriptional silencing by promoter hypermethylation is an important regulatory mechanism in tumorigenesis in many cancers. Therefore, the methylation level of the ADCYAP1 promoter was investigated in eight cervical cancer cell lines and human tissue samples with a distinctive degree of malignant transformation. While multiple CpG sites in the ADCYAP1 promoter were highly methylated in CIN III and invasive carcinoma cells as well as seven cervical cancer cell lines, they were rarely methylated in normal cells. Importantly, methylation in the ADCYAP1 promoter seems to start from CIN 1, relatively early stage of multistep carcinogenesis. This fact suggest that ADCYAP1 can be used as an effective and sensitive methylation biomarker for the early diagnosis of cervical cancer. Moreover, our data imply that the level of the ADCYAP1 promoter hypermethylation is correlated with cervical cancer development. We also show that ADCYAP1 gene expression was reactivated by the treatment of a DNA methyltransferase inhibitor of 5'-aza-2'deoxycytidine and/or a histone deacetylase inhibitor of trichostain A in cervical cancer cells suggesting that hypermethylation in the ADCYAP1 promoter is responsible for the transcriptional silencing of the ADCYAP1 gene in cervical cancer cells.