HDAC inhibitor-based therapies: can we interpret the code?

Abstract

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. One of the most promising approaches towards drugs that modulate epigenetic processes has been seen in the development of inhibitors of histone deacetylases (HDACs). HDACs regulate the acetylation of histones in nucleosomes, which mediates changes in chromatin conformation, leading to regulation of gene expression. HDACs also regulate the acetylation status of a variety of other non-histone substrates, including key tumour suppressor proteins and oncogenes. Histone deacetylase inhibitors (HDIs) are potent anti-proliferative agents which modulate acetylation by targeting histone deacetylases. Interest is increasing in HDI-based therapies and so far, two HDIs, vorinostat (SAHA) and romidepsin (FK228), have been approved for treating cutaneous T-cell lymphoma (CTCL). Others are undergoing clinical trials. Treatment with HDIs prompts tumour cells to undergo apoptosis, and cell-based studies have shown a number of other outcomes to result from HDI treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. However, our understanding of the key pathways through which HDAC inhibitors affect tumour cell growth remains incomplete, which has hampered progress in identifying malignancies other than CTCL which are likely to respond to HDI treatment.

Figure 1

Schematic organisation of classes I, II and IV HDACs showing their domain composition, size, cellular localization, target proteins and the cellular processes which are consequently regulated. The HDAC deacetylase catalytic domains are shown in purple, nuclear localization targeting sequences in yellow, and the ubiquitin‐binding BUZ domain of HDAC6 is in orange. A single substrate example is given alongside each enzyme, as well as the process in which this substrate participates.

Figure 2

Influence of HDACs on different cell biological processes and consequences of HDAC inhibition. HDACs are involved in many cellular processes, including progression through the cell cycle, cell differentiation and development, cell migration and motility, angiogenesis and autophagy. These processes could promote tumour cell survival, proliferation and metastasis. HDAC inhibition blocks some of these processes, indicated by red lines, or favours other processes such as apoptosis, here indicated by the green arrow.

Figure 3

Pleiotropic activities of HDAC6 in protein quality control. Misfolded proteins accumulate upon cellular stress or proteasome inhibition. These ubiquitinated misfolded proteins are recognized by HDAC6 and displace basal interactors of HDAC, in particular Hsp90, HSF1 and VCP. Subsequently, client proteins can be released from Hsp90, HSF1 can trimerize and act as a transcription factor on HSE determined proteins, e.g. Hsp70. VCP exerts its segregase activity and helps in DSB repair upon cellular stress. HDAC6 targets misfolded proteins to the MTOC via microtubules and is also involved in the process of autophagy.