Abstract
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. 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. 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. 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.
Highlights
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
We investigated the mRNA expression of all 11 non-sirtuin HDAC family members in large cohorts of primary neuroblastoma samples from the German Neuroblastoma trial using oligonucleotide microarray (n = 251) or real-time reverse transcription-PCR (RT-PCR) analysis (n = 118)
These results clearly show that among all 11 HDAC family members, only HDAC8 expression correlates with advanced disease stage but is low in stage 4S neuroblastoma known to be associated with spontaneous regression
Summary
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. 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 reproduced the HDAC8 knockdown phenotype. HDAC inhibitors have been shown to induce the inhibition of proliferation, apoptosis, and clonogenic growth and to promote differentiation in several cancer cell lines in vitro, and to exert antitumoral effects in mouse models [3, 4]. This work describes for the first time the clinical relevance of a particular HDAC family member, HDAC8, in a large study cohort of tumor patients using childhood neuroblastoma as a model. The selective targeting of HDAC8 causes the inhibition of cell proliferation and clonogenic growth and the induction of neuronal differentiation in culture models. The work opens novel antineuroblastoma treatment perspectives using selective HDAC8 small-molecule inhibitors
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