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Reactivating the expression of methylation silenced genes in human cancer
1Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, Utah, UT 84112, USA. adam.karpf@hci.utah.edu
Abstract:
DNA methylation alterations are now widely recognized as a contributing factor in human tumorigenesis. A significant number of tumor suppressor genes are transcriptionally silenced by promoter hypermethylation, and recent research implicates alterations in chromatin structure as the mechanistic basis for this repression. The enzymes responsible for catalyzing DNA-cytosine methylation, as well as the proteins involved in interpreting the DNA methylation signal, have now been elucidated. Technological advances, including gene expression microarrays and genome scanning techniques, have allowed the comprehensive measurement of DNA methylation changes in human cancers. An important distinction between DNA methylation (epigenetic) and mutation or deletion (genetic) tumor suppressor gene inactivation is that epigenetic inactivation can be abrogated by small molecules, including DNA methyltransferase and histone deacetylase inhibitors. Further, strategies have been developed that combine treatments with drugs that reactivate silenced gene expression with secondary agents that target the re-expressed genes and/or reconstituted signal transduction pathways. In this review, we will discuss in detail the mechanisms of gene silencing by DNA methylation, the techniques used to decipher the complement of methylation-inactivated genes in human cancers, and current and future strategies for reactivating the expression of methylation-silenced genes.
Insights
DNA methylation silences tumor suppressor genes in cancer. Epigenetic silencing can be reversed by drugs, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- DNA methylation is a key epigenetic mechanism implicated in human tumorigenesis.
- Promoter hypermethylation frequently leads to transcriptional silencing of tumor suppressor genes.
- Chromatin structure alterations are increasingly recognized as the basis for this gene repression.
Purpose of the Study:
- To review the mechanisms of gene silencing by DNA methylation in human cancers.
- To discuss techniques for identifying methylation-inactivated genes.
- To explore current and future strategies for reactivating these silenced genes.
Main Methods:
- Review of existing literature on DNA methylation and cancer.
- Discussion of technological advances like gene expression microarrays and genome scanning.
- Analysis of therapeutic strategies involving DNA methyltransferase and histone deacetylase inhibitors.
Main Results:
- DNA methylation alterations are a significant factor in cancer development.
- Epigenetic gene silencing by DNA methylation is potentially reversible.
- Combined therapeutic strategies targeting reactivated genes show promise.
Conclusions:
- Understanding DNA methylation mechanisms is crucial for cancer research.
- Epigenetic therapies offer a distinct approach to cancer treatment compared to traditional genetic interventions.
- Future research should focus on developing and refining strategies to reverse epigenetic silencing in cancer.