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

  title={Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?},
  author={Stephen B. Baylin and Joyce Ellen Ohm},
  journal={Nature Reviews Cancer},
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… 
Cancer epigenetics: from disruption of differentiation programs to the emergence of cancer stem cells.
It is speculated that epigenetic changes in stem cells and somatic cells contribute significantly to carcinogenesis by disruption of cellular differentiation programs.
Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis
A previously unsuspected epigenetic factor is described and the incorporation of the 11‐zinc finger CCCTC‐binding factor, known as CTCF is proposed as a novel and multifunctional epigenetic regulator.
Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials
The aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression are summarized and the development of inhibitors of or drugs targeted at epigenetic enzymes are highlighted.
The epigenetics of breast cancer
Small-molecular modulators of cancer-associated epigenetic mechanisms.
In this review, chemical epigenetics relevant to cancer therapy is dealt with, focusing especially on small molecules that regulate epigenetic mechanisms related to DNA methylation and histone modification.
Epigenetic aberrations during oncogenesis
A better understanding of the intertwined relationship between genetics, epigenetics and microRNAs is necessary in order to resolve how gene expression aberrations that contribute to tumorigenesis can be therapeutically corrected.
Epigenetic inactivation of DNA repair in breast cancer.
The Genetic-Epigenetic Interplay in Cancer
The Rb-ATM-DNMT1 nexus is discussed as a novel pathway linking genetic aberration of two genes commonly inactivated in human cancer into epigenetic events indispensable for tumor evolution.
Epigenetic regulation of gene expression in cancer: techniques, resources and analysis
Advances in bioinformatics data integration techniques that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer, and are therefore also a focus of this review.
The cancer epigenome--components and functional correlates.
An exciting emerging theme is that an understanding of stem cell chromatin control of gene expression, including relationships between histone modifications and DNA methylation, may hold a key to understanding the origins of cancer epigenetic changes.


The fundamental role of epigenetic events in cancer
This review discusses patterns of DNA methylation and chromatin structure in neoplasia and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
Cancer-epigenetics comes of age
Current mechanistic understanding of the role of DNA methylation in malignant transformation is reviewed, and it is suggested Knudson's two–hit hypothesis should be expanded to include epigenetic mechanisms of gene inactivation.
Epigenetics in human disease and prospects for epigenetic therapy
Great potential lies in the development of ‘epigenetic therapies’ — several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.
Gene silencing in cancer in association with promoter hypermethylation.
The mechanisms of gene silencing in cancer and clinical applications of this phenomenon are reviewed, especially tumor-suppressor genes.
A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer
Using cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer shows that this approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone.
Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene.
Distinct epigenetic changes in the stromal cells of breast cancers
A new method, methylation-specific digital karyotyping, was developed and applied to epithelial and myoepithelial cells, stromal fibroblasts from normal breast tissue, and in situ and invasive breast carcinomas and showed that distinct epigenetic alterations occur in all three cell types during breast tumorigenesis, suggesting that epigenetic changes have a role in the maintenance of the abnormal cellular microenvironment in breast cancer.
DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
It is demonstrated that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and compelling evidence that such methylation is essential for optimal neoplastic proliferation is provided.
Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis.
Findings support the notion of a dual role for DNA hypomethylation in suppressing later stages of intestinal tumorigenesis, but promoting early lesions in the colon and liver through an LOH mechanism.