Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape

Key Points Alterations in the epigenetic landscape are a hallmark of human cancer. Cancer-associated changes in the covalent modifications of DNA and histones may arise from mutations in, or the altered expression of, chromatin modifiers and/or non-coding RNAs. Recent studies show that the interplay between upstream signalling pathways and chromatin modifications represents an important mechanism controlling the cancer epigenome. Kinase signalling pathways can modify the epigenome via direct phosphorylation of histones or chromatin modifiers, leading to changes in chromatin structure and gene expression. These pathways can be hijacked by oncogenic mutations to aberrantly modulate chromatin modifications. Oncogenic signalling pathways can also contribute to cancer-specific methylation patterns by controlling global DNA methyltransferase activity or the accessibility of certain regulatory elements to DNA methylation. Histone modifications are involved in various cellular processes, including transcription activation, apoptosis, DNA repair and mitotic chromatin condensation. The dynamic process of phosphorylation (for example, at histones H3S10 and H3S28) can impair the deposition of potentially more stable methyl marks on adjacent lysine residues; such crosstalk can amplify the influence of signalling pathways on chromatin structure. Chromatin modifiers, such as enhancer of zeste homologue 2 (EZH2), BMI1, p300 and CREB binding protein (CBP), are phosphorylated by multiple upstream signalling kinases, indicating that they can function as points of convergence for these signalling pathways. The end result of these phosphorylation events can vary depending on their site-specific and cell type-specific context. The DNA damage response represents a major signalling pathway that alters chromatin structure via the phosphorylation of histones and histone modifiers. The decision of cells to undergo cell cycle arrest and repair damaged DNA or undergo cell death reflects the integration of various upstream signals. The interplay between signalling pathways and the epigenome may have important implications for therapeutic strategies for cancer. Treating tumour cells with kinase inhibitors may not be sufficient to restore the deregulated gene expression programmes that are found in these cells. Combining kinase inhibitors with epigenetically focused therapies may more effectively reverse the epigenetic features that maintain the transformed phenotype in cancer cells, leading to improved patient outcomes.