title: Hypermethylated in cancer 1 (HIC1), a tumor suppressor gene epigenetically deregulated in hyperparathyroid tumors by histone H3 lysine modification.
abstract: BACKGROUND
  Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance.
  
  
  OBJECTIVE
  The aim of the study was to investigate whether HIC1 may act as a tumor suppressor in the parathyroid glands and whether deregulated expression involves epigenetic mechanisms.
  
  
  METHODS
  Parathyroid tumors from patients with pHPT included single adenomas, multiple tumors 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, chromatin immunoprecipitation, and RNA interference was used.
  
  
  RESULTS
  HIC1 was generally underexpressed regardless of the hyperparathyroid disease state including multiple parathyroid tumors from the same patient, and overexpression of HIC1 led to a decrease in clonogenic survival of parathyroid tumor cells. Only the carcinomas showed a high methylation level and reduced HIC1 expression. Cell culture experiments, including use of primary parathyroid tumor cells prepared directly after operation, the general histone methyltransferase inhibitor 3-deazaneplanocin A, chromatin immunoprecipitation, and RNA interference of DNA methyltransferases and EZH2 (enhancer of zeste homolog 2), supported a role of repressive histone H3 modifications (H3K27me2/3) rather than DNA methylation in repression of HIC1.
  
  
  CONCLUSIONS
  The results strongly support a growth-regulatory role of HIC1 in the parathyroid glands and suggest that perturbed expression of HIC1 may represent an early event during tumor development. Repressive histone modification H3K27me2/3 is involved in repression of HIC1 expression in hyperparathyroid tumors.
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala University Hospital, Entrance 70, third floor, SE-75185 Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Svedlund
authors.forename: Susanne
authors.initials: S
authors.lastname: Koskinen Edblom
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Göran
authors.initials: G
authors.lastname: Åkerström
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westin
mesh_terms: D000236:Adenoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D044127:Epigenesis, Genetic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism / Q000502:physiology; D006657:Histones / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000150:complications / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008239:Lysine / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C499808:HIC1 protein, human; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine