“
“Background Bladder cancer is the seventh most common cancer type worldwide with about 300,000 newly diagnosed cases per year

[1]. One-third of the patients are diagnosed with a muscle invasive carcinoma and up to 50% of patients already present with or developed metastases within the first two years. While patients with a non-muscle invasive papillary urothelial carcinoma expect a rather good prognosis, long term survival of patients suffering from metastatic disease does not exceed 20% [2]. Although significant responses rates are observed after treatment with cisplatin based combination chemotherapy, find more the majority of patients will develop disease recurrence presenting with cisplatin resistance [3-5]. Epigenetic alterations have been proposed as a driving force of malignancy [6-8]. In particular, histone deacetylases (HDACs) are associated with the development and progression of several cancer types [9,10]. The human HDAC family is composed of 18 genes and is classified based on the sequence homology to their yeast orthologues

Rpd3, HdaI and Sir2 and their domain organization: HDAC1, HDAC2, HDAC3 and HDAC8 (class I); HDAC4, HDAC5, HDAC7 and HDAC9 (class IIa); HDAC6 and HDAC10 (class II NVP-HSP990 cell line b); HDAC11 (class IV) and seven sirtuins (class III) [11-13]. The classical HDACs catalyze the Zn2+ dependent deacetylation of acetyl-lysine residues [11]. Expression profiles Idoxuridine of class I HDACs are prognostic in various malignancies e.g. gastric, prostate and ovarian cancer [14-16]. In general, HDACs are considered to act as transcriptional co-repressors because high HDAC activity is associated with transcriptionally inactive chromatin [17,18]. Although many HDACs deacetylate histones the analysis of the human acetylome indicates that the deacetylation of non-histone proteins represents a considerable

part of their action [19,20]. Substrates include p53 [21], cohesion subunit SMC3 [22] and α-tubulin [23]. HDAC inhibitors are useful in the therapy of several hematological malignancies and are currently also investigated in the treatment of solid cancers [24,25]. The expression of HDAC8 has been described in a variety of cancer entities e.g. colon, breast lung, pancreas and ovary cancer [26]. HDAC8 is the most recently identified class I HDAC. It is a protein of 377 amino acids and contains a NLS in the center of the catalytic domain [27-29]. HDAC8 has a conserved motif for phosphorylation by protein kinase A (PKA), which negatively impacts its catalytic activity [30,31]. While class I HDAC family members form nuclear multiprotein complexes that interact with other chromatin modifiers and transcription factors, HDAC8 has not been found to do so [17]. Its intracellular localization seems to depend on the cell type.