Coregulomics: transcriptional co-regulator control of driver pathways in cancer
Large-scale sequencing and international GWAS efforts continue to identify common and rare genetic determinants of disease states. Given enough time and money all but the rarest of variants should be discovered and validated. Arguably to date we have already identified the most common aberrations in many cancer types e.g.: BRAF in melanoma and HER2 in breast cancer. However what is also becoming increasingly clear is that as rarer mutations are found we see that dysfunction may not be identical at the level of individual driver molecules but certainly in the same common ‘driver pathways’. These same pathway dysfunctions are shared between many cancer types and disease states. One beneficial upshot of this is that drugs developed as targeted therapy for one type of cancer are increasingly been used ‘off label’ to target the same pathway in other cancers. Nevertheless it is apparent that we need more innovative means to target driver pathways in cancer in a combination of ways that minimizes development of disease resistance.
- Coregulators as rheostats of cellular signaling
The ‘transcriptome’ determines the actions of given genome and while transcription factors are the molecular determinants of transcription, they are required to interact with a whole other class of proteins, transcriptional coregulators, to exert their myriad effects. Transcriptional coregulators comprise a family of many related and unrelated proteins, which often do not harbor DNA binding domains themselves but function within coregulator complexes of approximately 10 proteins. The coregulator complexes can be competitive or permissive resulting in enhanced or repressed target gene expression. The composition of a coregulator complex is dependent on tissue type and temporal availability of individual components, and can determine the specificity of the same given extracellular signal in different cellular contexts. In addition, coregulators often have intrinsic (or recruit other cofactors that have) histone modifying properties allowing them to control an associated transcription factors’ access to the genome and influence the epigenetic state of a variety of effector molecules. Additionally, some coregulators also have a role outside of the nucleus and in this way function to integrate genomic and extranuclear signaling pathways. To date, there have been over 350 coregulators described for the nuclear receptor superfamily alone but many of these also function as coregulators for other types of transcription factors.
- Coregulator pathology & molecular targeting
A number of cancer types have been defined by coregulator dysfunction and of the coregulators described to date well over half are directly associated with some disease state. There are almost 100 coregulator knockout phenotypes described in the literature and gene expression profiling analysis using publically available datasets paints a clear picture of a group of molecules whose expression is, more often that not, significantly altered in cancer. In the case of breast cancer particularly, dysregulation of coregulator expression is clearly linked to altered ERα signaling which ultimately determines clinical outcome. Owing to the central role of coregulator proteins in driver pathways in several hormone dependent cancers it has been proposed that development of coregulator targeting agents is one way to overcome the resistance seen when using the more traditional approach of targeting the steroid receptor (e.g: ERα in breast cancer and AR in prostate cancer). The rationale behind this is that the resistance pathways invoked by driver pathway blockade will still require many of the same coregulators of the original pathway. Despite this, molecular targeting of corepressor or coactivators functional domains remains a rather unexplored area with great potential for a wide range of disease states. Naturally a first step towards exploiting this potential is the characterization of the mechanism of action of individual coregulator proteins. Our research aims to address this need.