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

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

doi:10.18632/oncotarget.12936

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.

Highlights

Thyroid cancer originating from the thyroid epithelial cells is the most common endocrine malignancy
Statistical analysis confirmed that hypermethylated in cancer-1 (HIC1) expression in primary papillary thyroid carcinomas was significantly correlated with lymph node metastasis of thyroid cancer, age, and TNM staging, but not with sex, tumor size, or tumor capsular invasion (Table 1)
Previous studies have shown that hypermethylation of the HIC1 promoter and overexpression of HIC1 protein occurs in thyroid cancer cells [22]; but this is the first report that HIC1 promoter methylation in papillary thyroid carcinomas correlates with lymph node metastasis, tumor www.impactjournals.com/oncotarget stage, and patient age

Summary

Introduction

Thyroid cancer originating from the thyroid epithelial cells is the most common endocrine malignancy. Inactivation of HIC1 upregulates SIRT1 expression in both cancerous and normal cells and promotes tumorigenesis [16, 21]. Recent studies indicate that HIC1 methylation causes abnormal overexpression of SIRT, which contributes to the development and progression of breast [16], lung [17], and pancreatic cancers [10]

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Results

Conclusion