Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

Abstract

Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. Moreover, tumor growth and metastasis formation are signi®cantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy. Keywords: cancer therapy/HDAC inhibitor/histone deacetylase/leukemia/valproic acid IntroductionLocal remodeling of chromatin and dynamic changes in the nucleosomal packaging of DNA are key steps in the regulation of gene expression, consequently affecting proper cell function, differentiation and proliferation. One of the most important mechanisms in chromatin remodeling is the post-translational modi®cation of the N-terminal tails of histones by acetylation, which apparently contributes to a`histone code' determining the activity of target genes (Strahl and Allis, 2000). Acetylation of histones and possibly other substrates is mediated by enzymes with histone acetyltransferase (HAT) activity. Conversely, acetyl groups are removed by histone deacetylases (HDACs). Both HAT and HDAC activities are recruited to target genes in complexes with sequencespeci®c transcription factors and their cofactors, e.g. corepressors such as N-CoR and SMRT, and coactivators (Chen and Evans, 1995;Ho Èrlein et al., 1995;Xu et al., 1999). Nuclear receptors were the main examples of transcription factors recruiting HAT-and HDAC-associated cofactors depending on their status of activation by an appropriate ligand (Alland et al., 1997;Heinzel et al., 1997;Nagy et al., 1997;Glass and Rosenfeld, 2000). Other transcription factors such as Mad-1, BCL-6 and ETO have also been shown to assemble HDAC-dependent transcriptional repressor complexes (Laherty et al., 1997;Dhordain et al., 1998;Gelmetti et al., 1998;Lutterbach et al., 1998;Wang et al., 1998).Inappropriate repression of genes required for cell differentiation has been linked to several forms of cancer, particularly to acute leukemia. In acute promyelocytic leukemia (APL) patients, retinoic acid receptor (RAR) fusion proteins (e.g. PML±RAR or PLZF±RAR) resulting from chromosomal translocations can interact with components of the corepressor complex (Grignani et al., 1998;Guidez et al., 1998;He et al., 1998;Lin et al., 1998). The hypothesis that corepressor-mediated aberrant repression may be causal for pathogenesis in APL is supported by the ®nding that the differentiation block in cells transformed by PLZF±RAR is overc...

Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

“…Furthermore, in xenograft experiments in mouse, VPA was shown to decrease tumour growth combined with a more differentiated phenotype of the NB cells (Cinatl et al, 1997. The mechanisms behind these effects remained elusive until recent findings showed that VPA is a potent HDAC inhibitor and that induced differentiation of carcinoma and leukaemic cells could be associated to this activity (Gottlicher et al, 2001).…”

“…The mechanisms behind these effects are still not clear, but might involve the ERK-signalling cascade, cell-cycle regulatory proteins, inhibition of protein kinase C or activation of PPARg (Yuan et al, 2001;Blaheta and Cinatl, 2002;Gurvich et al, 2004). One important finding is however that VPA functions as an HDAC inhibitor, possibly by binding to the catalytic centre of HDACs (Gottlicher et al, 2001). Furthermore, it was shown that VPA induced differentiation of F9 teratocarcinoma and AML cells.…”

“…Furthermore, it was shown that VPA induced differentiation of F9 teratocarcinoma and AML cells. In addition, VPA delayed tumour formation in mouse xenograft experiments (Gottlicher et al, 2001). VPA has also been shown to suppress the malignant phenotype of NB cells, indicated by upregulation of some neuronal markers and decreased cell growth (Cinatl et al, 1997Yuan et al, 2001).…”

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

“…21 Recent studies demonstrate that glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase consisting of two isoforms and regulating an array of transcription factors, is a direct target of lithium, 23,24 while VPA inhibits histone deacetylase (HDAC), which has a prominent role in the regulation of gene expression. 25,26 Emerging evidence suggests that inhibition of GSK-3 and HDAC are responsible, at least in part, for the neuroprotective effects of lithium and VPA, respectively. 27,28 The present study was undertaken to investigate whether BDNF exon IV-containing mRNA and promoter IV activity are increased by lithium or VPA treatment in rat cortical neurons, and to determine the BDNF promoter region that confers the sensitivity to either drug.…”

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

“…3,4 HDAC has been catalogued into three classes (for a review, see Gray and Ekstrom 5 ). Class I HDACs consist of HDAC 1, 2, 3, and 8, whereas Class II HDACs include HDAC 4, 5, 6, 7, 9, and 10.…”