Abstract
BackgroundThyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways.MethodsExperiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A).ResultsApoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca2+ release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells.ConclusionsThe present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.
Highlights
Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation
hydroxy-7-(2-naphthylthio) hepatonomide (HNHA) inhibited the proliferation of anaplastic thyroid cancer (ATC) and papillary thyroid carcinoma (PTC) cells To investigate the anti-cancer activity of HNHA alongside two well-known histone deacetylase (HDAC) inhibitors (TSA and suberoylanilide hydroxamic acid) (SAHA)), we assayed ATC (SNU-80) and PTC (SNU-790) cell proliferation in the presence and absence of these compounds using an MTT assay (Table 1)
Further characterization of the effects of HDAC inhibitors on ATC and PTC cell viability showed that they all reduced the viability of ATC and PTC cells, as compared to vehicle control-treated cells
Summary
Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways. Thyroid cancer can be treated effectively with surgery or radioactive iodine [3]. Tumor dissemination occurs in this type of cancer, resulting in 40 % of patients showing distant metastases and 90 % showing invasion of adjoining tissue on presentation [7]. The present study investigated HDAC inhibitors as a novel chemotherapy for PTC and ATC. HDACs are often highly expressed in cancer cells [8,9,10].
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