Histone Acetylation and Cancer

Abstract

Acta Oncologica Vol. 42, No. 7, p. 792, 2003Received 7 March 2003Accepted 14 April 2003To the Editor:The organization of chromatin is crucial for the regulation of geneexpression. In particular, both the positioning and properties ofnucleosomes influence promoter-specific transcription in responseto extracellular or intracellular signals (1). There is a growing bodyof evidence to suggest that the acetylation and deacetylation ofhistones play significant roles in transcriptional regulation ofeukaryotic cells. To date, several papers have been published abouttheir role in gene expression (2). They are catalysed by specificenzyme families, histone acetyltransferases (HATs) and deacety-lases (HDACs). HATs have been identified as transcriptionalcoactivators and HDACs as yeast transcriptional regulators. Thereare at least four groups of proteins with intrinsic HAT activity,while eight HDACs belonging to three distinct classes have beendescribed in mammalian cells (1).The balance between acetylation and deacetylation is animportant factor in regulating gene expression and is thus linkedto the control of cell fate. Disruption of HAT or HDAC activity ispossibly associated with cancer development (3). Genes that encodeHAT enzymes are either translocated, or amplified, or over-expressed, or mutated in different types of cancers. Nucleosomescontaining highly charged hypoacetylated histones bind tightly tothe phosphate backbone of DNA, inhibiting transcription, pre-sumably because transcription factors, regulatory complexes andRNA polymerase do not have access to DNA. Acetylationneutralizes the charge of the histones and generates a more openDNA conformation. From molecular analyses of human diseases itis suggested that changes in acetylation may play a role in theuncontrolled cell growth of cancer. Since aberrant histone acetyla-tion has been linked to malignant diseases in some cases, HDACinhibitors have potential as new drugs due to their ability tomodulate transcription and to induce differentiation and apoptosis.Today’s treatment strategies are mostly limited to general HDACinhibitors, some of which have pleiotropic and/or unknown effectsin addition to deacetylase repression. Several drugs that are able toinhibit HDACs are at present undergoing clinical trials (4). Theseinclude short chain fatty acids (such as 4-phenylbutyrate andvalporic acid), hydroxamic acids (such as suberoylanilide hydro-xamic acid or SAHA, pyroxamide, trichostatin A or TSA,oxamflatin and CHAPs), cyclic tetrapeptides (such as trapoxin,apicidin and depsipeptide*