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Reduced Calcium Sensing Receptor (CaSR) Expression Is Epigenetically Deregulated in Parathyroid Adenomas

Priyanka Singh1, Sanjay Kumar Bhadada1, Divya Dahiya2

  • 1Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

The Journal of Clinical Endocrinology and Metabolism
|July 2, 2020
PubMed
Abstract

Insights

Epigenetic changes, including DNA hypermethylation and H3K9me3 modifications, silence calcium sensing receptor (CaSR) expression in parathyroid adenomas, contributing to parathyroid tumorigenesis.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Epigenetics

Background:

  • Reduced calcium sensing receptor (CaSR) expression is linked to parathyroid tumor development.
  • The precise epigenetic mechanisms driving CaSR dysregulation in parathyroid adenomas are not fully understood.

Purpose of the Study:

  • To investigate epigenetic alterations, specifically DNA methylation and histone modifications, affecting CaSR expression in sporadic parathyroid adenomas.
  • To correlate these epigenetic changes with clinical indicators of parathyroid disease.

Main Methods:

  • Analysis of CaSR mRNA and protein levels in 40 parathyroid adenomas and 10 controls using qPCR and immunohistochemistry.
  • Bisulphite sequencing to assess CaSR promoter 2 methylation.
  • Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) to evaluate histone modifications (H3K9me3).
  • In vitro studies using 5-aza-2'deoxycytidine to assess CaSR expression restoration.

Main Results:

  • Parathyroid adenomas exhibited significantly reduced CaSR mRNA (0.12-fold) and protein expression (in 90% of cases).
  • CaSR promoter 2 showed significant hypermethylation in 45% of adenomas compared to controls (6.7%), with maximum methylation at a GCM2 binding site.
  • Increased H3K9me3 enrichment (10-fold) was observed in adenomas, correlating with reduced CaSR mRNA.
  • CaSR promoter methylation correlated directly with plasma intact parathyroid hormone levels.
  • 5-aza-2'deoxycytidine treatment restored CaSR expression in a parathyroid cell line.

Conclusions:

  • Hypermethylation and increased H3K9me3 of the CaSR promoter 2 are key mechanisms contributing to CaSR silencing in sporadic parathyroid adenomas.
  • These epigenetic modifications play a significant role in parathyroid tumorigenesis.
Keywords:
5-aza 2 ʹ deoxycytidinecalcium sensing receptorglial cell missing 2histone methylationprimary hyperparathyroidismpromoter methylation

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