Cancer epigenetics: linking basic biology to clinical medicine - PubMed (original) (raw)

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Cancer epigenetics: linking basic biology to clinical medicine

Hsing-Chen Tsai et al. Cell Res. 2011 Mar.

Abstract

Cancer evolution at all stages is driven by both epigenetic abnormalities as well as genetic alterations. Dysregulation of epigenetic control events may lead to abnormal patterns of DNA methylation and chromatin configurations, both of which are critical contributors to the pathogenesis of cancer. These epigenetic abnormalities are set and maintained by multiple protein complexes and the interplay between their individual components including DNA methylation machinery, histone modifiers, particularly, polycomb (PcG) proteins, and chromatin remodeling proteins. Recent advances in genome-wide technology have revealed that the involvement of these dysregulated epigenetic components appears to be extensive. Moreover, there is a growing connection between epigenetic abnormalities in cancer and concepts concerning stem-like cell subpopulations as a driving force for cancer. Emerging data suggest that aspects of the epigenetic landscape inherent to normal embryonic and adult stem/progenitor cells may help foster, under the stress of chronic inflammation or accumulating reactive oxygen species, evolution of malignant subpopulations. Finally, understanding molecular mechanisms involved in initiation and maintenance of epigenetic abnormalities in all types of cancer has great potential for translational purposes. This is already evident for epigenetic biomarker development, and for pharmacological targeting aimed at reversing cancer-specific epigenetic alterations.

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Figure 1

Figure 1

In normal stem/progenitor cells, the promoter regions of many CpG island-containing developmental genes are marked by both active (trimethylated histone H3 lysine 4; H3K4me3) and repressive marks (trimethylated histone H3 lysine 27; H3K27me3), termed “bivalent chromatin” by Bernstein et al. . This chromatin pattern holds these genes in a low, poised transcription state to prevent premature lineage commitment. When the stem/progenitor cells respond to environmental cues and start to differentiate, a shift of the balance between the active and repressive epigenetic marks takes place with corresponding changes in chromatin architecture, leading to the silencing of stemness genes and upregulation of lineage-specific genes. However, repeated environmental stress such as chronic inflammation or accumulating reactive oxygen species (ROS) may promote clonal expansion of cells with genetic or epigenetic abnormalities, which then contribute to tumor initiation and progression. During this course of oncogenesis, the repressive marks in the promoter regions of tumor suppressor genes may recruit DNA methylation machinery to impose abnormal CpG island methylation on these genes leading to permanent gene silencing. At the same time, these epigenetic abnormalities may also contribute to activation of stem cell pathways, such as the Wnt pathway, and bestow self-renewing properties on cancer cells.

Figure 2

Figure 2

DNA methylation-mediated aberrant gene silencing in cancer involves transcriptional repressive complexes in the gene promoter region and interactions between DNA methylation machinery, chromatin modifiers (such as histone deacetylase, HDAC) and polycomb (PcG) proteins. Pharmacological inhibition of individual components in the repressive complex with DNMT inhibitors and HDAC inhibitors, either alone or in combination, may result in DNA demethylation and complex disintegration leading to reactivation of critical genes and reversal of genome-wide epigenetic alterations in cancer through resetting multiple cellular processes, including lineage commitment, immunomodulation, major cell signaling pathways, programmed cell death, and others. HAT: histone acetylase. Pol II: RNA polymerase II.

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