Hypermethylated in cancer 1 (HIC1), a tumour suppressor gene epigenetically deregulated in hyperparathyroid tumours by histone modification
J. Svedlund1, S. Koskinen Edblom1, V. Marquez2, G. Åkerström1, P. Björklund1 & G. Westin1
Primary hyperparathyroidism (pHPT) resulting from parathyroid tumours is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumour development as a result of calcium and vitamin D regulatory disturbance.
The aim of the study was to investigate whether HIC1 may act as a tumour suppressor in the parathyroid glands and whether deregulated expression involves epigenetic mechanisms.
Parathyroid tumours from patients with pHPT included single adenomas, multiple tumours from the same patient, and cancer. Hyperplastic parathyroid glands from patients with sHPT and hypercalcemia, and normal parathyroid tissue specimens were included in the study. Quantitative RT-PCR, bisulfite pyrosequencing, colony formation assay, ChIP, and RNAi was used.
HIC1 was generally underexpressed regardless of the hyperparathyroid disease state including multiple parathyroid tumours from the same patient, and overexpression of HIC1 lead to a decrease in clonogenic survival of parathyroid tumour cells. Only the carcinomas showed high methylation level and reduced HIC1 expression. Cell culture experiments, including use of primary parathyroid tumour cells prepared directly after operation, the general histone methyltransferase inhibitor DZNep, ChIP, and RNAi, supported a role of repressive histone H3 modification rather than DNA methylation in repression of HIC1.
The results strongly support a tumour suppressor role of HIC1 in the parathyroid glands and suggest that perturbed expression of HIC1 may represent an early event during tumour development. Repressive histone modifications are involved in repression of HIC1 expression in hyperparathyroid tumours.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.