Histone deacetylases and cancer: causes and therapies

Key Points Histone acetylation is determined by the activities of two classes of enzyme: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histones are the core protein components of nucleosomes and their acetylation status regulates, in part, gene expression. Deacetylated histones are generally associated with silencing gene expression; so the acetylation of histones is generally associated with derepression of gene expression. Aberrant acetylation is associated with several solid tumours and haematological malignancies. Several types of compound have been identified that inhibit HDACs and cause accumulation of acetylated histones in normal and tumour tissues. They also inhibit transformed cell growth in vitro and in vivo . Inhibition of HDACs with hydroxamic-acid-based hybrid polar compounds — for example, suberoylanilide hydroxamic acid (SAHA) — alters transcription of very few expressed genes. Several HDAC inhibitors are in clinical trials with cancer patients. They are well tolerated, cause accumulation of acetylated histones in peripheral mononuclear cells and tumours and, more importantly, have clinical activity with objective tumour regression. Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?