14 R. Macri, M. Costilla, A. Klecha et al.
onset and progression of cancer due to its important role in the regulation
of gene expression. Methylation and acetylation of histones induce
changes in the structure of chromatin that can repress or facilitate the
expression of genes. Another epigenetic modification studied in recent
years is the methylation of DNA. Recently it has been observed that there
are abnormal patterns of DNA methylation in many types of cancers. The
malignant cells are accompanied by a global hypomethylation that is
associated with the activation of genes required for the invasion and
metastasis and a local hypermethylation (CpG Islands) associated with
the repression of tumor suppressor genes (TSGs). Thus, the methylation
of the TSG blocks its expression, contributing to the onset and tumor
progression. Classic examples are the genes BRCA1, PRC, TP53 and
PRDM in breast, colon, skin and lung cancer, respectively.
The abnormal patterns of DNA methylation, as well as epigenetic
modifications on histones, could be used as biomarkers for the diagnosis
of cancer and as targets of drugs, in order to correct these alterations and
restore the function of the genes. This chapter analyses the current
evidence on the role of epigenetic mechanisms involved in the
progression of various types of cancer and their clinical relevance.Keywords: Epigenetic, DNA-methyltransferases, histone deacetylases, tumor
suppressor genes, tumor progression
INTRODUCTION
Epigenetic and genetic alterations are two independent mechanisms that
have an important role in the modification of gene expression that are involved
in the onset and progression of cancer. Epigenetic changes can be as important
as the genetic mechanisms in the regulation of gene expression.
Cell proliferation is a process strongly regulated by various enzymes such
as cyclins dependent-kinases (CdKs) and proteins encoded by tumor
suppressor genes (TSG). In normal cells, the variations in the levels of
expression of CdKs regulate entry to the different phases of the cell cycle
while the proteins encoded by the TSG stop the cell cycle progression in
response to DNA damage or signals of the extracellular medium.
The loss of TSG function by deletions, mutations or epigenetic
modifications prevents the cell response to cell cycle checkpoints or cell death
by apoptosis if the DNA damage is high. This leads to an increase in mutations
and uncontrolled cell division.