title: HDAC2 promotes cell migration/invasion abilities through HIF-1α stabilization in human oral squamous cell carcinoma.
abstract: BACKGROUND
  Histone deacetylase 2 (HDAC2) expressions in oral squamous cell carcinoma (OSCC) had been implicated in advanced stage and poor prognosis. It suggests a possible link between the migration/invasion potential of oral cancer cells and the prevalent expression of HDAC2.
  
  
  METHODS
  Five head and neck cancer (HNC) cell lines, including Ca9-22, Cal-27, HSC-3, SAS, and TW2.6, were used. Cells stably overexpressing HDAC2 and shRNA against HDAC2 were established to investigate migration/invasion ability in vitro and tumorigenesis and progression in vivo.
  
  
  RESULTS
  We found that alterations in the HDAC2 level in OSCC cell lines modulated their invasive ability with a positive correlation. Animal model also showed that knockdown of HDAC2 expression in SAS cells, originally containing high endogenous HDAC2 expression, resulted in decrease in tumor initiation and progression. Using high-throughput transcriptome analysis, numerous genes involved in HIF-1α-associated pathways were found. At the mechanism levels, using agents to block de novo protein synthesis or prevent protein degradation by ubiquitination, we found the stability of hypoxia inducible factor 1α (HIF-1α) protein was maintained in OSCC cells with HDAC2 overexpression. In addition, co-immunoprecipitation assay also revealed that HDAC2-mediated HIF-1α protein stability is because of direct interaction of HIF-1α with von Hippel-Lindau (VHL) protein.
  
  
  CONCLUSIONS
  Our work demonstrates that HDAC2 maintains HIF-1α stability, probably at the level of protein modification, which in turn leads to the increase in cell invasion/migration ability in oral cancer progression. These findings implicate the potential of HDAC inhibitors for oral cancer therapy.
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Been-Ren
authors.initials: BR
authors.lastname: Lin
authors.forename: Szu-Ta
authors.initials: ST
authors.lastname: Chen
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Hsieh
authors.forename: Yue-Ju
authors.initials: YJ
authors.lastname: Li
authors.forename: Mark Y P
authors.initials: MY
authors.lastname: Kuo
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011897:Random Allocation; D054875:Ubiquitination / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; C497446:VHL protein, human; D008239:Lysine