Histone deacetylase 8 in neuroblastoma tumorigenesis.
OBJECTIVE
The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis.


METHODS
We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models.


RESULTS
Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment.


CONCLUSIONS
Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.
Oehme
Ina
I
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany.
Deubzer
Hedwig E
HE
Wegener
Dennis
D
Pickert
Diana
D
Linke
Jan-Peter
JP
Hero
Barbara
B
Kopp-Schneider
Annette
A
Westermann
Frank
F
Ulrich
Scott M
SM
von Deimling
Andreas
A
Fischer
Matthias
M
Witt
Olaf
O
D002454:Cell Differentiation / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016019:Survival Analysis
D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases