Histone deacetylase 8 in neuroblastoma tumorigenesis
Ina Oehme1, Hedwig E Deubzer, Dennis Wegener
1Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany.
Purpose:
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.
Experimental Design:
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.
Insights
Histone deacetylase 8 (HDAC8) plays a key role in neuroblastoma development. Targeting HDAC8 with specific inhibitors shows promise for differentiation therapy in neuroblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Histone deacetylases (HDACs) regulate fundamental cancer processes like cell cycle, differentiation, and apoptosis.
- Pan-HDAC inhibitors lack specificity, limiting understanding of individual HDAC roles in tumorigenesis.
- The specific contribution of each HDAC family member to neuroblastoma progression remains largely unknown.
Purpose of the Study:
- To investigate the role of individual HDACs in the development of neuroblastoma.
- To identify specific HDAC family members involved in neuroblastoma pathogenesis.
Main Methods:
- Analyzed mRNA expression of HDAC1-11 in a large cohort of primary neuroblastoma samples.
- Correlated HDAC expression with disease stage and patient survival.
- Functionally evaluated key HDACs using neuroblastoma cell culture models.
- Utilized HDAC8 knockdown and selective small-molecule inhibitors for functional studies.
Main Results:
- HDAC8 expression significantly correlated with advanced disease, metastasis, and poor survival.
- HDAC8 was downregulated in stage 4S neuroblastoma, associated with spontaneous regression.
- HDAC8 knockdown or inhibition reduced proliferation, clonogenic growth, and induced cell cycle arrest and differentiation.
- Global histone 4 acetylation remained unaffected by HDAC8 modulation.
Conclusions:
- HDAC8 is a critical factor in neuroblastoma pathogenesis.
- HDAC8 represents a specific and promising drug target for neuroblastoma differentiation therapy.
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