title: The histone methyltransferase EZH2, an oncogene common to benign and malignant parathyroid tumors.
abstract: 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. The aim of this study was to investigate a potential role of the histone 3 lysine 27 methyltransferase EZH2 in parathyroid tumorigenesis. Parathyroid tumors from patients with pHPT included adenomas and carcinomas. Hyperplastic parathyroid glands from patients with HPT secondary to uremia and normal parathyroid tissue specimens were included in this study. Quantitative RT-PCR, western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference were used. EZH2 was overexpressed in a subset of the benign and in all malignant parathyroid tumors as determined by quantitative RT-PCR and western blotting analyses. Overexpression was explained by EZH2 gene amplification in a large fraction of tumors. EZH2 depletion by RNA interference inhibited sHPT-1 parathyroid cell line proliferation as determined by tritium-thymidine incorporation and colony formation assays. EZH2 depletion also interfered with the Wnt/β-catenin signaling pathway by increased expression of growth-suppressive AXIN2, a negative regulator of β-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphoylated) β-catenin in the parathyroid tumor cells. To our knowledge EZH2 gene amplification presents the first genetic aberration common to parathyroid adenomas, secondary hyperplastic parathyroid glands, and parathyroid carcinomas. This supports the possibility of a common pathway in parathyroid tumor development.
authors.affiliation: Department of Surgical Sciences, Endocrine Unit, Uppsala University, Uppsala University Hospital, Entrance 70, 3 tr, SE-751 85 Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Svedlund
authors.forename: Elham
authors.initials: E
authors.lastname: Barazeghi
authors.forename: Peter
authors.initials: P
authors.lastname: Stålberg
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
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 / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000235:genetics*; D009857:Oncogenes; D010280:Parathyroid Glands / Q000378:metabolism*; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D012333:RNA, Messenger; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Axin2; EZH2; PRC2; gene amplification; hyperparathyroidism; β-catenin