title: Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer.
abstract: BACKGROUND
  Thyroid 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.
  
  
  METHODS
  Experiments 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).
  
  
  RESULTS
  Apoptosis, 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 Ca(2+) 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.
  
  
  CONCLUSIONS
  The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. SEOKMOKIM@yuhs.ac.
authors.forename: Seok-Mo
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. ggiru95@yuhs.ac.
authors.forename: Ki-Cheong
authors.initials: KC
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Yonsei College of Medicine, Seoul, 120-752, South Korea. JYJEON@yuhs.ac.
authors.forename: Jeong-Yong
authors.initials: JY
authors.lastname: Jeon
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. KIMBOB95@yuhs.ac.
authors.forename: Bup-Woo
authors.initials: BW
authors.lastname: Kim
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. 0267660@yuhs.ac.
authors.forename: Hyeung-Kyoo
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. DOCJANG@yuhs.ac.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Chang
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. shchoi@yuhs.ac.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. CSPARK1@yuhs.ac.
authors.forename: Cheong-Soo
authors.initials: CS
authors.lastname: Park
authors.affiliation: Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, 135-720, South Korea. SURGHSC@yuhs.ac.
authors.forename: Hang-Seok
authors.initials: HS
authors.lastname: Chang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D009281:Naphthalenes / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C520433:N-hydroxy-7-(2-naphthylthio)heptanamide; D009281:Naphthalenes; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; D002118:Calcium