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  • Review Article
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Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?

Key Points

  • Epigenetic gene silencing, which is associated with aberrant methylation of promoter DNA and transcriptional repression, is an important mechanism for the loss of gene function in cancer.

  • Silencing can occur during the early stages of human tumour progression — in pre-invasive lesions — and involves disruption or over-activation of key developmental pathways and cell-signalling properties.

  • These early gene-silencing events might be crucial for inducing the aberrant, early, clonal expansion of cells through the above alterations in key cell pathways.

  • Early gene-silencing events might 'addict' cells to certain oncogenic pathways. This 'epigenetic addiction' could predispose cells to the accumulation of genetic mutations in these same pathways, which drives tumour progression.

Abstract

Chromatin alterations have been associated with all stages of tumour formation and progression. The best characterized are epigenetically mediated transcriptional-silencing events that are associated with increases in DNA methylation — particularly at promoter regions of genes that regulate important cell functions. Recent evidence indicates that epigenetic changes might 'addict' cancer cells to altered signal-transduction pathways during the early stages of tumour development. Dependence on these pathways for cell proliferation or survival allows them to acquire genetic mutations in the same pathways, providing the cell with selective advantages that promote tumour progression. Strategies to reverse epigenetic gene silencing might therefore be useful in cancer prevention and therapy.

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Figure 1: Addiction to the Wnt signalling pathway through gene-silencing events.
Figure 2: Epigenetic silencing of HIC1 and control of DNA-damage responses.
Figure 3: Epigenetic gene-silencing events and tumorigenesis.
Figure 4: Overview of the polycomb repressive complexes (PRCs).

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Acknowledgements

The authors thank all of their colleagues whose work has contributed to the concepts in this review. Portions of the work cited has been supported by grants to S.B.B. from the National Cancer Institute and the National National Institute of Environmental Health Sciences.

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Stephen B. Baylin is a consultant to OncoMethylome Sciences. Under licensing agreement between the Johns Hopkins University and this company, M.S.P. was licensed to OncoMethylome Sciences and they are entitled to a share of the royalties received by the University from sales of the licensed technology. Also, S.B.B. is a consultant for and received research support from BioNumerik Pharmaceuticals, Inc.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

lung cancer

myelodysplasia

osteosarcoma

ovarian cancer

prostate cancer

Wilms tumour

FURTHER INFORMATION

Chromatin Structure and Function page

Gene Silencing

Science epigenetics site

The Wellcome trust

Glossary

CpG islands

Regions of DNA that are often located proximally to the transcription start site of genes that contain a high frequency of CG dinucleotides. In most mammalian genes, these regions are normally maintained free of DNA methylation. In cancer cells, CpG islands of various tumour-suppressor genes are frequently densely methylated, which results in repression of transcription.

DNA-demethylating agents

5-aza-deoxycytidine and 5-aza-cytidine are drugs that can induce DNA demethylation and are clinically effective as treatment for the pre-leukaemic syndrome myelodysplasia. They incorporate into DNA in place of cytidine, and can then bind and irreversibly inhibit DNA methyltransferases.

Atypical crypt foci

Pre-adenomatous, pre-malignant, hyperplastic cells that are derived from individual villus crypts. They are thought to constitute pre-malignant lesions with a risk of progression to colon cancer.

Heritable repression

Epigenetic repression that is passed, through division, from cell to daughter cell.

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Baylin, S., Ohm, J. Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?. Nat Rev Cancer 6, 107–116 (2006). https://doi.org/10.1038/nrc1799

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