title: Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma.
abstract: Hypermethylation leading to the loss of hypermethylated in cancer-1 (HIC1) gene expression occurs in many different types of human cancer. HIC1 is a transcriptional repressor that directly binds to the promoter region of NAD-dependent deacetylase sirtuin-1 (SIRT1). SIRT1 functions in cell growth, is anti-apoptotic, protect neurons, functions in senescence, and regulates energy restriction. Epigenetic modification and dysregulation affecting the HIC1/SIRT1 axis is potentially important for the development of malignancies. However, the importance of HIC1 expression in the development of papillary thyroid carcinoma, especially in Chinese patients, is uncertain. Therefore, we assessed the level of methylation in the HIC1 promoter and the mRNA and protein expression levels of HIC1 and SIRT1 in human thyroid papillary carcinoma and tumor adjacent control tissues. The demethylation reagent 5-aza-2'-deoxyctidine (5-aza-dc) and an HIC1 overexpression plasmid were used to manipulate the HIC1/SIRT1 pathway, and the effects on cell senescence, apoptosis, and cell cycle progression were assessed. Compared to normal thyroid tissue, thyroid tumors had lower expression of HIC1 and higher SIRT1 expression. The level of HIC1 methylation was also higher in thyroid carcinoma tissues than adjacent tissues. HIC1 expression was closely correlated with patient age and tumor progression. Restoration of HIC1 expression through an overexpression plasmid or 5-aza-dC treatment reduced SIRT1 expression and cell proliferation, and led to senescence, cell cycle arrest, and apoptosis. Aberrant expression of HIC1/SIRT1 and hypermethylation of the HIC1 promoter may be critical for the development and progression of papillary thyroid cancer.
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Wenyi
authors: W
authors: Wu
authors: Endocrine Department, The 180th Military Hospital of Chinese Peoples, Liberation Army, Quanzhou, Fujian, China.
authors: Liting
authors: L
authors: Zhang
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Jianqing
authors: J
authors: Lin
authors: Endocrine Department, Affiliated Zhongshan Hospital of Guangdong Medical College, Zhongshan, Guangdong, China.
authors: Hanwei
authors: H
authors: Huang
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Bai
authors: B
authors: Shi
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Xingong
authors: X
authors: Lin
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Zhongxin
authors: Z
authors: Huang
authors: Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Chaoyang
authors: C
authors: Wang
authors: Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
authors: Jianlong
authors: J
authors: Qiu
authors: Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors: Xiaolong
authors: X
authors: Wei
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D000077209:Decitabine; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D001374:Azacitidine
keywords: HIC1; SIRT1; papillary thyroid carcinoma; promoter hypermethylation