title: HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth.
abstract: OBJECTIVE
  Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth.
  
  
  METHODS
  Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells.
  
  
  RESULTS
  HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability.
  
  
  CONCLUSIONS
  HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany. t.milde@dkfz.de
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Paul
authors.initials: P
authors.lastname: Northcott
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012306:Risk; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D012097:Repressor Proteins; C404500:HDAC5 protein, human; C486544:HDAC9 protein, human; D006655:Histone Deacetylases