Abstract
The processed pseudogene PTENP1 is involved in the regulation of the expression of the PTEN and acts as a tumor suppressor in many types of malignances. In our previous study we showed that PTENP1 methylation is present not only in tumor, but also in normal endometrium tissues of women over 45 years old. Here we used methylation-specific PCR to analyze methylation status of CpG island located near promoter region of PTENP1 in malignant and non-malignant endometrium tissues collected from 236 women of different age groups. To confirm our results, we also analyzed RNA sequencing and microarray data from 431 women with endometrial cancer from TCGA database. We demonstrated that methylation of PTENP1 is significantly increased in older patients. We also found an age-dependent increase in the level of PTENP1 expression in endometrial tissue. According to our data, PTENP1 methylation elevates the level of the pseudogene sense transcript. In turn, a high level of this transcript correlates with a more favorable prognosis in endometrial cancer. The data obtained suggested that PTENP1 methylation is associated with age-related changes in normal and hyperplastic endometrial tissues. We assumed that age-related increase in PTENP1 methylation and subsequent elevation of its expression may serve as a protective mechanism aimed to prevent malignant transformation of endometrial tissue in women during the perimenopause, menopause, and postmenopause periods.
Highlights
Methylation of cytosine at position 5 with the formation of 5-methylcytosine (5mC) is one of the most frequent epigenetic modifications of DNA in eukaryotes [1]
In total we studied 14 conventional cell lines, three of which (HaCaT, HEK-293, MCR-5) were noncancerous and the remaining ones were related to pancreatic adenocarcinoma (AsPC-1, COLO-357, T3M4, BxPC-3), breast cancer (MCF-7, BT-474, HBL-100, and SKBR3), cervical cancer (HeLa), ovarian cancer (SKOV-3), and a hepatocellular carcinoma (HepG2)
Since we found an age-dependent increase in the frequency of methylation of PTENP1 in normal and hyperplastic endometrium, we suggested that the level of expression of the pseudogene should change with age in these tissues
Summary
Methylation of cytosine at position 5 with the formation of 5-methylcytosine (5mC) is one of the most frequent epigenetic modifications of DNA in eukaryotes [1]. There are tissue-specific methylation patterns of the CpG sequences located at gene promoter regions, the so-called CpG islands (CGI). These patterns change in the course of ontogenesis and are often associated with suppression of transcription of relevant genes [2,3]. In the process of aging of an organism, total genomic DNA methylation level gradually decreases (a process known as global hypomethylation) while certain genetic loci are being selective hypermethylated. Correlations observed between the level of methylation of individual genetic loci and chronological age of the organism triggered formation of an independent area of researches aimed to develop an epigenetic clock that would allow determining true biological age [10,11]. Since the signs of accelerated aging can be associated with many diseases, analysis of methylation of the above-mentioned sequences can be used for evaluation of the real biological age and prediction of pathology progression [14]
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