16 R. Macri, M. Costilla, A. Klecha et al.
inactivation. Conversely, aberrant methylation patterns participate in the
promotion of some diseases, including cancer.
In cancer cells, epigenetic alterations that have been found most often
involve hypomethylation of DNA sequences normally methylated and the
aberrant hypermethylation of the usually non-methylated sequences.
Hypomethylation and hypermethylation occur at specific sites in the genome,
but these are different depending on the type of tumor cell. While
hypomethylation of usually methylated regions is associated with the
activation of genes required for the invasion and metastasis, the
hypermethylation in promotor regions of genes suchs as cell cycle regulatory
proteins and TSG is correlated with transcriptional inactivation and
carcinogenesis in many types of cancers. In this regard, regulators of the cell
cycle, such as p16, p21, p27 and p53, have been found silenced by methylation
mechanisms in many cancers. Aberrant hypermethylation inactivate genes
related to the control of the cell cycle, apoptosis and DNA repair. Epigenetic
silencing of TSG by promoter hypermethylation is associated with increased
tumor severity and poor survival 5 .
In general it has been observed a low degree of DNA methylation in
human tumors, favoring the transcription of genes that normally are not
expressed.
In opposition, an aberrant hypermethylation that inhibits the expression of
TSG, such as BRCA1, PRC, TP53 and PRDM has been observed in breast,
colon, skin and lung cancer, respectively. This knowledge has various
applications, changes in the patterns of methylation or modifications in
histones can be used as biomarkers for the diagnosis of several types of cancer.
So, for example, the RARβ gene methylation is useful in the detection of
prostate cancer and the PRDM gene methylation is used as a predictor of the
response to chemotherapy drugs.
The miRNA are small non-coding RNA molecules that interact with its
mRNA target, inhibiting its transcription. Evidence shows that the
hypermethylation of the miRNA can downregulate its function and contribute
to the generation of cancer. This is another important epigenetic mechanism
that is deregulated in cancer.
The potentially reversible state of the epigenetic alterations generates
targets for therapeutic strategies to restore the normal epigenetic patterns.
Also, enzymes that mediate the epigenetic processes such as the histone
acetyltransferases (HATs), histone deacetylases (HDACs) and DNA
methyltransferases (DNMTs) are being analized as potential targets of
anticancer drugs.