Histone deacetylase inhibitors and cancer therapy

Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research and understanding epigenetic control has supplied a plethora of potential targets for intervention in cancer. Histone deacetylases (HDACs) have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. Here, we review HDAC inhibitors, together with their current status of clinical development and potential utility in cancer therapy

Histone deacetylase inhibitors in psoriasis therapy

Psoriasis is recognised as a multifactorial disease with inflammatory, proliferative, angiogenic and genetic components contributing to the pathology. The disease, which may vary in intensity, remains clinically unmet although there have been several recent advances that have had a substantial impact on suffering. Histone deacetylase inhibitors represent a new class of therapeutic agent, initially developed for oncology, which prevent cell proliferation and induce differentiation. Here we discuss the possible application of HDAC inhibitors to psoriasis, focussing particularly on their anti-proliferative and anti-inflammatory activity. Our view, based upon the emerging clinical properties of HDAC inhibitors, reflects the growing recognition that HDAC inhibitors will be important therapeutic agents in diseases other than cancer

The p53 response: Emerging levels of co-factor complexity

DNA damage triggers a checkpoint response that involves a myriad of cellular responses including cell cycle arrest, DNA repair, and apoptosis, and defects in the DNA damage response pathway lead to tumour development [1]. The tumour suppressor protein p53 is a key player in the checkpoint response to DNA damage, and the precise regulation of p53 is critical for both the checkpoint response and the suppression of tumourigenesis. This is highlighted by the fact that the p53 gene is one of the most commonly mutated genes in human cancer; approximately 50% of human cancers contain p53 mutations while the other half are thought to contain alterations in components of the p53 pathway [2]. p53 is a nuclear transcription factor that affects cellular functions which include transcription, DNA synthesis and repair, cell cycle arrest, senescence, and apoptosis [3]. The central region of p53 contains the DNA-binding domain (DBD), the amino (N)-terminal region harbours a transcriptional activation domain together with a polyproline-rich region, and the carboxyl (C)-terminal region contains a regulatory domain which includes a nuclear localisation signal (NLS) and an oligomerisation function [4]. Under normal conditions, p53 is held in a latent inactive state but undergoes a significant increase in protein stability upon exposure to DNA damage. DNA damage stabilises p53 in part via the DNA damage signalling pathway that involves the sensor kinases, including ATM and ATR, and effector kinases, like Chk1 and Chk2, which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis [1] and [4]. Since the activation of p53 causes cell cycle arrest and apoptosis, aberrant activation of p53 would have dire consequences for an organism. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. Whilst post-translational modification plays an important role in p53 regulation [5], an increasing array of co-factors are now known to influence p53 activity. Here, we will discuss our current understanding of the emerging co-factor complexity involved in regulating the p53 response

The cell cycle and drug discovery: The promise and the hope

In recent years, there have been major developments in the understanding of the cell cycle. It is now known that normal cellular proliferation is tightly regulated by the activation and deactivation of a series of proteins that constitute the cell cycle machinery. The expression and activity of components of the cell cycle can be altered during the development of a variety of diseases where aberrant proliferation contributes to the pathology of the illness. Apart from yielding a new source of untapped therapeutic targets, it is likely that manipulating the activity of such proteins in diseased states will provide an important route for treating proliferative disorders, and the opportunity to develop a novel class of future medicines

p300/CBP proteins: HATs for transcriptional bridges and scaffolds

p300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription apparatus, allowing the appropriate level of gene activity to occur in response to diverse physiological cues that influence, for example, proliferation, differentiation and apoptosis. p300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumour-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription apparatus. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumour suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control

Signalling DNA damage by regulating p53 co-factor activity

In response to DNA damage the related phosphatidylinositol-3-OH-kinase-like-kinases ATM and ATR phosphorylate downstream protein targets which facilitate the DNA damage response. A new pathway in which ATM phosphorylates the transcriptional co-factor strap has been elucidated. Phosphorylation causes the stabilization of nuclear Strap and favours the formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Most interestingly, in AT cells Strap remains cytoplasmic, and a mutant derivative that cannot be phosphorylated by ATM is similarly localised to the cytoplasm. These results argue that Strap is an important downstream effector in the DNA damage response

Histone deacetylase inhibitors open new doors in cancer therapy

Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research has supplied a plethora of potential targets for intervention in cancer. Here, we focus on the histone deacetylase (HDAC) inhibitors, together with their current status of clinical development and potential utility in cancer therapy. HDACs have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. We discuss the rationale for the development of HDAC inhibitors as novel anti-cancer agents, the potential clinical application and explore ideas on how we may move towards patient stratification with the possibility of increasing efficacy in the clinic

Control of gene expression and the cell cycle

The pRb tumour suppressor protein is an essential component of the cell-cycle clock, integrating both positive and negative signals for cellular growth and proliferation with the transcription machinery. pRb exerts its tumour suppression function by both antagonizing and synergizing with downstream effectors, such as E2F. pRb has two modes of action, it can inactivate E2F transcription activity or it can assemble an active repression complex with E2F. Apart from E2F, pRb interacts with various factors to promote cellular differentiation. The differentiation properties of pRb are likely to contribute partly to its tumour suppressor function. It is also clear that pRb is a master regulator for transcription. It can both activate and repress transcription in a context-dependent manner. pRb interacts directly with histone acetyltransferase, histone deacetylases and SWI/SNF proteins, all of which are classes of proteins involved in chromatin remodelling. Last, but not least, pRb regulates transcription driven by all three polymerases, thereby integrating the cell-cycle clock with the biosynthetic capacity of the cell in controlling cellular proliferation and growth

Role of LXCXE motif-dependent interactions in the activity of the retinoblastoma protein

Cell cycle control by pRb requires the integrity of the pocket domain, which is a region necessary for interactions with a variety of proteins, including E2F and LXCXE-motif containing proteins. Through knowledge of the crystal structure of pRb we have prepared a panel of pRb mutant derivatives in which a cluster of lysine residues that demark the LXCXE peptide binding domain were systematically mutated. One of the mutant derivatives, Rb6A, exhibits significantly reduced LXCXE-dependent interactions with HPV E7, cyclinD1 and HDAC2, but retained LXCXE-independent binding to E2F. Consistent with these results, Rb6A could down-regulate E2F-1-dependent activation of different E2F responsive promoters, but was compromised in Rb-dependent repression. Most importantly, Rb6A retained wild-type growth arrest activity, and colony forming activity similar to wild-type pRb. It is compatible with these results that directly targeting HDAC2 to E2F responsive promoters as an E2F/HDAC hybrid protein failed to effect cell cycle arrest. These results suggest that LXCXE-dependent interactions are not essential for pRb to exert growth arrest