Turning genes on to turn cancer off
In 2006, the drug decitabine (Dacogen) joined its sister molecule azacytidine (Vidaza) as an approved treatment for myelodysplastic syndromes—diseases of the blood-forming cells of the bone marrow that can progress to leukemias.
What’s interesting about these two drugs is how they work: they both “turn on” genes that have been aberrantly silenced in cancer cells, putting them in a new class of drugs called “epigenetic therapies.”
“Epigenetics” refers to the control of gene expression by mechanisms “in addition to” (from the Greek epi) the DNA sequence.
In general, chemical “tags,” added like bracelet charms to DNA or to histone proteins around which DNA winds in the nucleus, regulate whether genes are expressed (turned on) or silenced (turned off). These epigenetic tags are influenced by the environment—hormone levels, diet, drugs—and can be passed to daughter cells during cell division.
They are key to cell identity—a stem cell does not turn on the same genes as a mature brain cell, for example—and they change with time. A study published in 2005 by Manel Esteller, M.D., Ph.D., and colleagues at the Spanish National Cancer Center in Madrid showed that identical twins who share the same genome are “epigenetically indistinguishable” in their early years. But as they age, their epigenetic tags diverge, potentially explaining differences in disease susceptibility.
Epigenetic changes are increasingly being linked to cancer.
“Almost all cancers that have been studied have an epigenetic component to them,” says Peter Jones, Ph.D., D.Sc., director of the University of Southern California/Norris Comprehensive Cancer Center in Los Angeles.
The best-characterized epigenetic change in cancer is the “hypermethylation” of promoter regions—the addition of many chemical “methyl” groups to the areas of DNA that control gene expression.
Hypermethylation inappropriately silences genes, particularly so-called tumor suppressor genes that normally put the brakes on uncontrolled cell growth. Mutations in the DNA sequence of such genes cause inherited forms of cancer. And now we know that silencing of the same genes by hypermethylation can also cause sporadic forms of cancer, Jones says.
The good news, he adds, is that an epigenetic modification like hypermethylation is “a treatable defect.” That’s where the drugs Vidaza and Dacogen come in, reversing the hypermethylation and turning silenced genes back on.
Jones demonstrated this mechanism in 1980. He and colleagues had shown first that Vidaza and related drugs could turn on genes, and later that they did so by inhibiting DNA methylation.
“When those two processes were tied together, it gave people a tool to really start looking at the relationship between gene expression and DNA methylation,” Jones says.
Vidaza and Dacogen are now joined by a lengthy list of DNA methylation inhibitors and chromatin-modifying drugs that are in preclinical and clinical testing. Chromatin is the DNA-histone protein complex.
“We’re just beginning this era of epigenetic drugs,” Jones says.
DNA methylation and other epigenetic “biomarkers” may also be useful for early cancer detection, diagnosis, and prognosis.
Wael El-Rifai, M.D., Ph.D., and colleagues at the Vanderbilt-Ingram Cancer Center have noted DNA hypermethylation of several genes in Barrett’s esophagus—a change in the cells lining the esophagus that can progress to esophageal adenocarcinoma. The frequency of hypermethylation increases as the cells progress from Barrett’s esophagus to dysplasia (pre-cancerous condition) to adenocarcinoma.
“Promoter DNA hypermethylation is an early change in tumorigenesis, and it’s a progressive one,” says El-Rifai, professor of Surgery and Cancer Biology.
It’s now time, Jones and other contend, to engage in a Human Epigenome Project, an effort to identify and understand all of the chemical tags that coordinate expression of genes.
“It’s critically important that we understand the human epigenome: it’s at the heart of what stem cells are, it’s an essential component of aging, and it’s of major importance in human diseases, particularly cancer,” Jones says. “We’re going ahead full speed.”
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