Targeting histone deacetylases in neuroblastoma.
Histone deacetylases (HDACs) are an emerging class of novel anti-cancer drug targets. Recently, studies in adult cancers and in neuroblastoma have shown that individual HDAC family members are aberrantly expressed in tumors and correlate with disease stage and prognosis. In neuroblastoma, knockdown of individual HDAC family members causes distinct phenotypes ranging from differentiation to apoptosis. HDACs are involved in controlling MYCN function and are upregulated in chemotherapy-resistant neuroblastoma cells. Treatment with unselective pan-HDAC inhibitors causes cell cycle arrest, differentiation, apoptosis, and inhibition of clonogenic growth of neuroblastoma cells, and restores susceptibility to chemotherapy treatment. The molecular mechanisms mediating the anti-cancer effects of HDAC inhibitors on neuroblastoma cells are incompletely understood and involve targeting of aberrant epigenetic repression of tumor suppressor genes, activation of developmental differentiation pathways, as well as changing the acetylation level and function of non-histone proteins. In neuroblastoma mouse models, unselective HDAC inhibitors demonstrate anti-tumoral effects. First phase I clinical trials in children with refractory cancers using HDAC inhibitors depsipeptide and the recently approved vorinostat are underway. This review summarizes our current knowledge about classical HDAC family members as novel drug targets for neuroblastoma therapy and discusses the potential role of next generation, selective HDAC inhibitors.
Witt
O
O
CCU Pediatric Oncology, German Cancer Research Center and Department of Pediatric Oncology, Hematology, Pneumonology and Immunology, University Hospital of Heidelberg, Germany. o.witt@dkfz.de
Deubzer
H E
HE
Lodrini
M
M
Milde
T
T
Oehme
I
I
D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases