Epigenetic Aberrations in Cancer: A Prelude or Conclusion?
Do genetic mutations cause cancer, with epigenetic changes following suit, or is the process of cellular transformation kicked off by epigenetic dysregulation, with mutations ensuing therefrom? For years researchers have viewed cancer as a genetic disease, but as new epigenetic datasets continue to pour out of labs worldwide, the textbooks might need some more updating.
In a recent review, Flora Chik and her colleagues at the Department of Pharmacology and Therapeutics at McGill University’s Faculty of Medicine take a look at some of latest evidence pinning epigenetics in both the initiation and progression of cancer.
Epigenetics in Cancer Initiation
In the past, cancer has been closely tied to genetic mutations. These mutations impact various regulatory cascades, ultimately enabling cells to thrive rather than die, but there are exceptions.
Some tumors, like malignant rhabdoid tumors (MRTs), are often found with an inactivated Snf5 tumor suppressor gene, the protein product of which is part of chromatin remodeling complexes. Unlike other tumors, MRT tumors display healthy genomes, providing evidence that an aberrant epigenome can lead to cancers in cells with intact genomes.
More evidence supporting epigenetic-driven cancer is provided in colon cancers, where global hypomethylation and regional promoter hypermethylation have been found in pre-cancerous regions and benign polyps before they turned malignant.
Additional studies in breast cancer have found that even some nearby normal tissue surrounding tumors have the same pattern of global hypomethylation and selective regional hypermethylation found in malignant tumors.
Other studies have shown elevated mutation rates as the result of global hypomethylation.
Such observations suggest that epigenetic changes such as methylation loss may occur before genetic instability and transformation, rather than as a consequence.
Epigenetics in Metastasis
In the review, Chik highlights that epigenetic mechanisms could play a role after initiation as well. Tumor cells of epithelial origin such as breast and prostate will often change their cytoskeletal components, lose their polarity, and become insensitive to the hormones that once regulated them, in a process called epithelial-to-mesenchymal transition (EMT).
Some of the genes commonly affected during EMT include those with CpG islands in their promoters, meaning they can be regulated epigenetically.
Among the silenced genes are those coding for the adhesion molecule E-cadherin, and for an antagonist of the WNT signaling pathway implicated in tumor growth and invasion. There are also several mesenchymal-specific genes that are turned on during EMT which contain large CpG islands found to be more demethylated in more aggressive tumors.
For nascent cancer cells to break free from their surroundings and invade new territory, they typically need to degrade the extracellular matrix (ECM). The ECM protease uPA, which can initiate a cascade resulting in proteolysis of a series of ECM proteins, has been implicated in promoting tumor invasion.
In most normal tissue, uPA is nearly undetectable, and the uPA promoter contains a large CpG island which is methylated. Studies have found uPA to be methylated in non-invasive tumor cell lines, but fully demethylated in more aggressive lines.
Setting Cancer Straight
Epigenetic modifications, unlike genetic ones, can be reversed. Opposing forces like methylation and demethylation, and their ramifications and mechanisms, are receiving increasing scrutiny in cancer research. Tools to alter the balance have even moved from laboratory investigations to clinical trials and treatments.
5-azaCdR, for example, is FDA-approved for use as a demethylating agent. During DNA replication the cytidine analog is incorporated into newly formed dsDNA. It forms covalent bonds with and sequesters DNMTs. The problem is that 5-azaCdR works non-specifically on the whole DNMT family, leading to a global loss of methylation. This has led to some unwelcome consequences, such as increased cell invasion and metastasis, presumably due to an increase in expression of various oncogenes.
As the field progresses, it will need to develop solutions like more targeted DNMT inhibitors and more specific methylating agents, and/or work with combinations of agents that in concert can find just the right balance.
Read the full review in Advances in Experimental Medicine and Biology, 2011.
News Provided by NCBI