Cancer Epigenetics Laboratory; Spanish National Cancer Centre (CNIO)
The disruption of the genomic DNA methylation patterns was the first epigenetic abnormality described in human cancer. This imbalance results in promoter CpG island hypermetylation of tumor suppressor genes, leading to transcriptional repression and global genomic hypomethylation which ultimately causes chromosomal instability and reactivation of endoparasitic sequences. The relationship between DNA methylation and histone modifications was initially described for the inactivation of the X chromosome in females, and for the demonstration of strong interactions between the DNA methylation machinery and the chromatin modifiers. It was also shown that the repression of tumor suppressor genes by promoter hypermethylation is associated with a specific histone modification index. In this jigsaw, a global view was missing on how the histone modification landscape was distorted in the cancer cells. We have recently provided this piece of the puzzle by demonstrating that the association between DNA methylation and histone modification aberrations in cancer also occurs at the global level. In human and mouse tumors, histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively. Most importantly, these alterations occur within the context of the repetitive DNA sequences that also become hypomethylated in transformed cells. The global alterations of histone acetylation status suggest novel pathways through which histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) may function as tumor suppressor genes or oncogenes. In this regard, we have shown in leukemias that the generation of particular fusion proteins involving HATs is associated with an erasure of the monoacetylated lysine 16-H4 mark. Other authors have postulated that the loss of trimethylation at lysine 20-H4 might disrupt heterochromatic domains, and reduce the response to DNA damage in cancer cells.