Abstract
Cyclin D1, a G1-S phase regulator, is upregulated in parathyroid adenomas. Since cyclin-dependent kinase (CDK) inhibitors, CDKN2A and CDKN2B, and RASSF1A (Ras-association domain family 1, isoform A) are involved in G1-S phase arrest and act as potential tumor suppressor genes, we aimed to study potential methylation-mediated inactivation of these genes in parathyroid adenomas. Gene expressions of cyclin D1 (CCND1) and regulatory molecules (CDKN2A, CDKN2B and RASSF1A) was analysed in parathyroid adenoma tissues (n = 30). DNA promoter methylation of cyclin D1 regulators were assessed and correlated with clinicopathological features of the patients. Gene expression analysis showed a relative fold reductions of 0.35 for CDKN2A (p = 0.01), 0.45 for CDKN2B (P = 0.02), and 0.39 for RASSF1A (p < 0.01) in adenomatous compared to normal parathyroid tissue. There was an inverse relationship between the expressions of CDKN2A and CDKN2B with CCND1. In addition, the promoter regions of CDKN2A, CDKN2B, and of RASSF1A were significantly hyper-methylated in 50% (n = 15), 47% (n = 14), and 90% (n = 27) of adenomas respectively. In contrast, no such aberrant methylation of these genes was observed in normal parathyroid tissue. So, promoter hypermethylation is associated with down-regulation of CCND1 regulatory genes in sporadic parathyroid adenomas. This dysregulated cell cycle mechanism may contribute to parathyroid tumorigenesis.
Highlights
Primary Hyperparathyroidism (PHPT) is characterized by hypercalcemia associated with elevated or non-suppressed serum parathyroid hormone (PTH) levels[1]
In this study we found that the promoter region of the three genes (CDKN2A, CDKN2B and RASSF1A) examined in sporadic parathyroid adenomas is frequently hypermethylated with the resultant reduced expression of their respective gene products
We have demonstrated an inverse relationship between expressions of the cyclin-dependent kinase (CDK) inhibitors and cyclin D1 in the adenomatous compared to the normal parathyroid tissue
Summary
Primary Hyperparathyroidism (PHPT) is characterized by hypercalcemia associated with elevated or non-suppressed serum parathyroid hormone (PTH) levels[1]. During progression of cell cycle, cyclin D1 binds to cyclin dependent kinases (CDKs) CDK4 and CDK6 These kinases compete with the CDK inhibitors, p16 and p15, and block the binding of CDKs to cyclin D1 resulting in G1 phase arrest. P16 and p15 proteins are encoded respectively by CDKN2A and CDKN2B, and act as tumor suppressor genes[9, 10] Reduced expression of these inhibitor proteins in parathyroid adenomas does not appear to be due to either deletion or mutations in these genes[11], but epigenetic changes, such as DNA methylation, could have a major role in the transcriptional silencing of gene expression. In the present study we analysed the expression patterns of three potential tumor suppressor genes, CDKN2A, CDKN2B and RASSF1A, in sporadic parathyroid adenomas. We further examined the methylation status of CpG sites in promoter regions of these genes as a potential epigenetic modification to explain their reduced expression patterns
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