Epigenetic Silencing of TTF-1/NKX2-1 Through DNA Hypermethylation and Histone H3 Modulation in Thyroid Carcinomas
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Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, is a homeodomain containing transcriptional factor identified in thyroid, lung and central nervous system. In the thyroid, TTF-1 is essential for thyroid organogenesis and governs thyroid functions by regulating various thyroid-specific genes. We previously demonstrated that most differentiated thyroid neoplasms, including follicular adenomas/carcinomas and papillary carcinomas, express TTF-1 at both protein and mRNA levels. However, certain subtypes of thyroid cancers have shown low or negative expression of TTF-1. The aim of our study was to investigate the function of epigenetic modification in dysregulation of TTF-1 in thyroid carcinoma cells. We evaluated the expression of TTF-1 in primary thyroid tissues (normal thyroid, papillary carcinoma and undifferentiated carcinoma) and in thyroid carcinoma cell lines using immunohistochemistry and RT-PCR. Methylation-specific PCR targeting CpG islands of TTF-1 and chromatin immunoprecipitation (ChIP) for histone H3 lysine 9 (H3-lys9) were applied to clarify the correlation of the TTF-1 expression profile and epigenetic status. We also explored whether epigenetic modifiers, including 5-aza-deoxycytidine, could restore TTF-1 expression in thyroid carcinoma cells. In our current study, immunohistochemistry and RT-PCR showed positive expression of TTF-1 in normal thyroids and papillary carcinomas. Meanwhile, most of the undifferentiated carcinomas and the cell lines lost TTF-1 expression. No methylation in the CpG of TTF-1 promoter was detected in normal thyroids or papillary carcinomas. In contrast, DNA methylation was identified in 60% of the undifferentiated carcinomas (6/10) and 50% of the cell lines (4/8). ChIP assay demonstrated that acetylation of H3-lys9 was positively correlated with TTF-1 expression in thyroid carcinoma cells. Finally, DNA demethylating agents could restore TTF-1 gene expression in the thyroid carcinoma cell lines. Our data suggest that epigenetics is involved with inactivation of TTF-1 in thyroid carcinomas, and provide a possible means of using TTF-1 as a target for differentiation-inducing therapy through epigenetic modification.
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PMID: 37560303 PMC: 10409498. DOI: 10.3389/fendo.2023.1130794.
Epigenetic Targets and Their Inhibitors in Thyroid Cancer Treatment.
Zhang K, Wang J, He Z, Qiu X, Sa R, Chen L Pharmaceuticals (Basel). 2023; 16(4).
PMID: 37111316 PMC: 10142462. DOI: 10.3390/ph16040559.
Zhu X, Zhao L, Doolittle W, Cheng S Endocr Relat Cancer. 2023; 30(6).
PMID: 36939877 PMC: 10354538. DOI: 10.1530/ERC-22-0306.
Yang T, Li J, Zhuo Z, Zeng H, Tan T, Miao L iScience. 2022; 25(7):104655.
PMID: 35811845 PMC: 9263519. DOI: 10.1016/j.isci.2022.104655.