Epigenetic activation of genes in cancer

Coolen, Marcel 2013

In a recent paper in Cancer Cell, Marcel Coolen (Dept. Human Genetics) together with Australian collaborators from Sydney's Garvan Institute of Medical Research, demonstrate that large regions of the genome - amounting to roughly 2% - are epigenetically activated in prostate cancer. The activated regions contain many prostate cancer-specific genes, including PSA (prostate specific antigen) and PCA3, the most common prostate cancer markers. Until now, these genes were not known to be regulated epigenetically. A previous study by Marcel Coolen and colleagues showed that similarly large regions of the prostate cancer genome are also epigenetically silenced, demonstrating a structured rearrangement of the cancer epigenome.

The new study remarkably shows that DNA methylation can activate genes, often by changing the gene start site, overturning the prevailing dogma that DNA methylation can only silence genes. The findings as a whole have extensive ramifications for cancer diagnosis and treatment, including epigenetic-based gene therapies, as they require the targeting of domains of genes, as opposed to single genes. By changing the methylation status of CpG islands that are very near to transcription start sites, but not overlapping, genes can be switched on. Secondly, the new study shows that the prostate cancer genome contains domains that harbour functionally unrelated genes are coordinately regulated in the cancer genome suggesting the presence of epigenetic 'master controllers' that can switch on or off very large regions of DNA. These findings will have a significant impact on our understanding of diagnostic tests and on chemotherapy treatment.

Cancer Cell, Epub ahead of print Dec 2012. http://www.sciencedirect.com/science/article/pii/S1535610812004862


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