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Blocking demethylase may drive melanoma cells into dormancy

Inhibiting the action of demethylase enzymes appears to re-activate epigenetic ‘tags’ in melanoma cells, forcing those cells into a dormant state, researchers report in Cancer Cell (Feb. 12, 2018; 33(2):322–336).

The authors note that cellular senescence is a state in which cells stop dividing and is one of the body’s defences against abnormally replicating cells. This hibernation-like condition is controlled by epigenetic ‘tags’ that control how the genetic information encoded by the DNA is actually used. However, in cancer cells, these tags are disabled.

The investigators examined approximately 500 skin samples excised from melanoma patients. Roughly one-third of the samples exhibited elevated demethylase activity which was impairing the ability of the cells to enter senescence.

Further experiments in melanoma cell cultures as well as mice and zebrafish with malignant melanoma, in which the researchers genetically modified the activity of the demethylase enzymes, as well as chemically blocking the activity of the enzymes, resulted in these interventions causing the sample cells to enter senescence, preventing them from further dividing.

Similar results were seen in mice that had human melanoma tissue implanted in them—a finding the authors say is important for future human applications.

As well, the researchers observed that in the mice with implanted melanoma cells, immune cells migrated into the tumour tissue once the senescence process had been reactivated by medication.

“We think the combined use of demethylase blockers and targeted immunotherapy might be extremely effective [for treating melanoma],” said study author Dr. Clemens Schmitt, in a press release. Dr. Schmitt is a clinical oncologist and researcher, and vice director of the division of hematology, oncology and tumour immunology at Charité—Universitätsmedizin Berlin, the Max Delbrück Center for Molecular Medicine.

These findings are particularly promising for the treatment of melanoma, the authors note, as it responds poorly to chemotherapy and is often more effectively treated with immunotherapies. Dr. Schmitt and his colleagues now want to see how well immunotherapy and senescence-inducing therapy can be combined in clinical trials, according to the release.

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