Epigenetic breakdown of cancer cells: From DNA methylation to histones
The disruption of DNA methylation was the first epigenetic abnormality described in human cancer. This imbalance consists in the promoter CpG island hypermetylation of tumor suppressor genes leading to transcriptional repression and global genomic hypomethylation leading to chromosomal instability and reactivation of endoparasitic sequences. Our results show that CpG island promoter hypermethylation has a tumor-type specific pattern, where each gene tends to be methylated in the cancer cells driven from a particular tissue but not from others. Epigenetic silencing affects all cellular pathways: DNA repair (hMLH1, MGMT, BRCA1), cell cycle (p16INK4a, p14ARF, p15INK4b, p73), apoptosis (DAPK, TMS1), hormone receptors (ER, PR, AR, RARB2, CRBP1), cell adherence (CDH1, TIMP3), detoxifiers (GSTP1) and many more (APC, LKB1, SOCS-1). Promoter hypermethylation of genes have important consequences for the biology of that particular tumor. This is for example the case of the DNA repair gene MGMT which methylation-mediated silencing leads to transition mutations, but, at the same time, “marks” those neoplasms that are going to be more sensitive to the chemotherapy with alkylating drugs. Hypermethylation can be observed in hereditary tumors, where it may account for the “second hit” of the tumor suppressor gene. We have also shown that the repression of tumor suppressor genes by promoter hypermethylation is associated with a specific histone modification index. In human tumors histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively, within the context of the repetitive DNA sequences that also becomes hypomethylated in transformed cells. In this regard, in leukemias the generation of particular fusion proteins involving HATs is associated with an erasure of the monoacetylated lysine 16-H4 mark and the loss of trimethylation at lysine 20-H4 might disrupt of heterochromatic domains and reduce the response to DNA damage of cancer cells.