Epigenetics Changes in Cancer Cells

Highlights of the American Association for Cancer Research Special Conference on Chromatin, Chromosomes, and Cancer Epigenetics; November 10-14, 2004; Waikoloa, Hawaii

Kris Novak, PhD

In This Article

Mechanisms of Epigenetic Gene Silencing

In the opening lecture, Stephen Baylin,[2] of Johns Hopkins University, Baltimore, Maryland, provided an overview of the basic mechanisms underlying epigenetic gene silencing. Genes can be silenced via hypermethylation of their promoter regions -- untranscribed regions of the genes that turn on and off their transcription.[3] This methylation commonly occurs at DNA sequences called "CpG islands," which are frequently found in gene promoters but can also occur in other areas of a chromosome.

In cancer cells, hypermethylation is frequently detected in the promoter regions of genes that control processes, such as proliferation, apoptosis, DNA repair, and immortalization. The silencing of genes that regulates these processes can therefore promote tumor formation and growth. For example, methylation silencing of SFRP genes, whose products antagonize the WNT signaling pathway, leads to cell proliferation and the formation of early dysplastic colon mucosal lesions in mice. Methylation of the cyclin-dependent kinase inhibitor p16Ink4 gene, which is a tumor suppressor, leads to immortalization of breast and lung epithelial cells -- the earliest steps toward becoming a cancer cell. And the gene encoding the detoxification enzyme glutathione S-transferase (GSTP1) is hypermethylated and inactivated in the majority of prostate cancers.

Little is known about how genes become silenced, or inactivated, via methylation during transformation. Many studies have shown that the activity levels of enzymes known as DNA methyltransferases (DNMTs), which add methyl groups to DNA at cytosine residues, are altered in tumor cells and are associated with several developmental abnormalities. In human cancer cells, the selective depletion of DNMT1 and DNMT3 enzymes induces demethylation and reactivation of silenced tumor suppressor genes, such as CDKN2A, p16Ink4, and GATA, in colon and bladder cancer cell lines.

Histones and other proteins mediate DNA compaction into chromatin. When histones are acetylated at specific amino acids by histone acetyltransferases, the chromatin takes on a relaxed, or open conformation (also called "euchromatin"), allowing the transcription factors to access the DNA and genes to be expressed. When histones are deacetylated via enzymes known as histone deacetylases (HDACs), the chromatin becomes closed (also called "heterochromatin"), blocking transcription factor access and gene expression. Like DNMTs, changes in the activity level of HDACs may alter the transcription of genes that controls cell-cycle progression and developmental events.

As a result, a variety of inhibitors have been developed to inhibit DNA methylation or histone deacetylation in cancer cells. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago when their methylation-inhibitory activities, even at low concentrations, were described for the first time. Although both of these agents had originally been administered at high doses, the redevelopment of these agents for low-dose schedules has shown clinical activities. 5-Azacytidine is now approved for the treatment of myelodysplastic syndromes and has shown activity in patients with acute myeloid leukemia (AML).

HDAC inhibitors, such as trichostatin and butyrate, can inhibit cancer cell proliferation, induce apoptosis, and regulate the expression of genes involved in the cell cycle. Although the precise mechanism underlying HDAC inhibitor-induced cell-growth arrest is not fully understood, the induction of genes that regulate cell-cycle progression, such as p21(CIP/WAF), is thought to be important. Studies have shown that in human colon cancer cell lines, trichostatin and butyrate treatment induced the expression of tumor suppressor genes, leading to cell-cycle arrest.

Epigenetic alterations are useful not only as therapeutic targets, but also in determining patient prognosis and predicting response to therapy. Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, which encodes a DNA-repair enzyme, inhibits the killing of tumor cells by alkylating agents. Studies have shown that methylation of the MGMT promoter in patient glioma samples is a useful predictor of the responsiveness of the tumors to alkylating agents. When this gene is silenced by methylation, patients are likely to have a better outcome after therapy.[4] The effects of gene silencing on tumor formation and growth can therefore be both positive and negative.


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