The analysis of mRNA levels of 11 classical HDAC family members in primary neuroblastomas has revealed a significant role of HDAC8 in neuroblastoma biology (Oehme et al. 2009). High levels of HDAC8 mRNA correlate with metastasizing and advanced stage disease with poor prognosis (stage 4), whereas in early stage neuroblastomas (stage 1) HDAC8 levels were downregulated. Importantly, stage 4S neuroblastomas associated with spontaneous regression express low levels of HDAC8 (Oehme et al. 2009). Functional studies in neuroblastoma cell lines have demonstrated that selective targeting of HDAC8 by RNAi as well as a small-molecule inhibitor reduces proliferation and induces differentiation of neuroblastoma cells. In contrast, knockdown of HDAC2 results in apoptosis of neuroblastoma cells indicating individual roles of different HDACs in neuroblastoma pathogenesis (Oehme et al. 2009). In addition, increased levels of HDAC1 mRNA have been found in multidrug-resistant neuroblastoma cell lines and siRNA-mediated knockdown of HDAC1 restores sensitivity of the cells to chemotherapeutic agents (Keshelava et al. 2007). The role of HDAC1 in neuroblastoma has been attributed to N-Myc-mediated gene regulation. For instance, N-Myc has been shown to recruit HDAC1 to Sp1 binding site of transglutaminase 2 (TG2) promoter, which results in transcriptional repression of TG2 gene (Liu et al. 2007).

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