Research Papers:

Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma

Wenyi Wu, Liting Zhang, Jianqing Lin, Hanwei Huang, Bai Shi, Xingong Lin, Zhongxin Huang, Chaoyang Wang, Jianlong Qiu and Xiaolong Wei _

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Oncotarget. 2016; 7:84416-84427. https://doi.org/10.18632/oncotarget.12936

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Wenyi Wu1,*, Liting Zhang2,*, Jianqing Lin1, Hanwei Huang3, Bai Shi1, Xingong Lin1, Zhongxin Huang1, Chaoyang Wang1, Jianlong Qiu4, Xiaolong Wei5

1Department of general surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China

2Endocrine Department, The 180th Military Hospital of Chinese Peoples, Liberation Army, Quanzhou, Fujian, China

3Endocrine Department, Affiliated Zhongshan Hospital of Guangdong Medical College, Zhongshan, Guangdong, China

4Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China

5Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China

*These authors contributed equally to this work

Correspondence to:

Xiaolong Wei, email: [email protected]

Wenyi Wu, email: [email protected]

Keywords: HIC1, SIRT1, papillary thyroid carcinoma, promoter hypermethylation

Received: April 21, 2016     Accepted: October 21, 2016     Published: October 26, 2016


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.

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