Transcription factor co-repressors in cancer biology: roles and targeting

Abstract

Normal transcription displays a high degree of flexibility over the choice, timing and magnitude of mRNA expression levels that tend to oscillate and cycle. These processes allow for combinatorial actions, feedback control and fine-tuning. A central role has emerged for the transcriptional co-repressor proteins such as NCOR1, NCOR2/SMRT, CoREST and CTBPs, to control the actions of many transcriptional factors, in large part, by recruitment and activation of a range of chromatin remodeling enzymes. Thus, co-repressors and chromatin remodeling factors are recruited to transcription factors at specific promoter/enhancer regions and execute changes in the chromatin structure. The specificity of this recruitment is controlled in a spatial-temporal manner. By playing a central role in transcriptional control, as they move and target transcription factors, co-repressors act as a key driver in the epigenetic economy of the nucleus. Co-repressor functions are selectively distorted in malignancy, by both loss and gain of function and contribute to the generation of transcriptional rigidity. Features of transcriptional rigidity apparent in cancer cells include the distorted signaling of nuclear receptors and the WNTs/beta-catenin axis. Understanding and predicting the consequences of altered co-repressor expression patterns in cancer cells has diagnostic and prognostic significance, and also have the capacity to be targeted through selective epigenetic therapies.

Figure 1. A model for the deregulation of co-repressors leading to stable targeted repression

Panel A. In normal systems the balance of co-activator (CoA) and co-repressor (CoR) expression are in dynamic equilibrium (left) such that they are rapidly recruited to and released from transcription factor (TF) complexes to control tightly the underlying epigenetic events. Such a dynamic choreography can give rise to patterns of mRNA expression that are alternating, or cycling. The net result is the rapidly responsive and alternating kinetics of mRNA expression (right). Panel B. Elevated CoR expression in malignancy limits the extent of the transcriptional cycle and reduces the peak height and accentuates the minima. Panel C. The sustained expression of CoRs generates a repressive chromatin environment that can selectively attract the CpG methylation machinery and lead to transcriptional silencing that is stably inherited and complete attenuation of transcriptional responsiveness.