Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins

Key Points Transcriptional programmes established during embryogenesis are transmitted to daughter cells of the adult so that each cell maintains its appropriate identity, a process referred to as cellular or transcriptional memory. Loss of cellular memory can lead to the spurious transcription of oncogenes and silencing of tumour suppressors, which predisposes to cancer. Polycomb group (PcG) and trithorax group (TrxG) proteins affect covalent modifications of histone tails, the position or composition of nucleosomes, as well as DNA methylation, thereby affecting chromatin structure and so transcriptional status. In general, PcG proteins repress — whereas TrxG proteins activate — gene expression. Gain of PcG and loss of TrxG function occurs in various human cancers, which is consistent with the idea that tumour cells have stem-like characteristics. This concept is supported by the observation that tumour cells have gene expression profiles that are similar to that of embryonic cells. The balance between PcG and TrxG proteins affects the expression of genes that induce cellular senescence — a tumour suppressive mechanism that opposes cellular proliferation. PcG–TrxG-mediated chromatin dynamics affects the expression of genes that regulate apoptosis, a process that controls unscheduled cellular proliferation by inducing cell death. PcG proteins can recruit proteins that transcriptionally silence genes encoding components of the apoptotic machinery. PcG–TrxG complexes function to maintain the integrity of the genome. The observation that loss of TrxG chromatin remodelling proteins predispose to cancer, even in the absence of genomic lesions, implies that modulation of PcG–TrxG function can be used to treat cancer. Polycomb and trithorax group proteins have opposing effects on chromatin, and either repress or activate gene expression, respectively. Therefore, the dynamic interplay between these protein families has complex effects on epigenetic regulation and consequently tumour biology. The discovery that cancer can be governed above and beyond the level of our DNA presents a new era for designing therapies that reverse the epigenetic state of a tumour cell. Understanding how altered chromatin dynamics leads to malignancy is essential for controlling tumour cells while sparing normal cells. Polycomb and trithorax group proteins are evolutionarily conserved and maintain chromatin in the 'off' or 'on' states, thereby preventing or promoting gene expression, res