In this study, researchers have succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes responsible for erasing epigenetic marks at the DNA. This discovery has potential for use in future combination therapies. The study is published in the journal Cancer Cell.
Genetic or pharmacological inhibition of these enzymes restarts the protective mechanism. Cellular senescence, a state in which cells terminally cease to divide prevents mutated cells from turning into tumors. This natural protective mechanism puts cells into a hibernation-like condition and is controlled by epigenetic tags located on the protein building blocks the DNA is wrapped around.
Demethylase blockers halt malignant melanoma
The research team conducted its study on almost 500 tissue samples taken from patients with black skin cancer, also known as melanoma. In roughly a third of the samples, researchers found a significant increase in the production of the demethylase enzymes able to stop the protective mechanism.
In melanoma cell cultures as well as mice and zebrafish with malignant melanoma, the researchers genetically modified the activity of these enzymes. They also used chemical agents to target and block them, which caused the cells to fall into the sleep-like state of senescence, thus stopping them to further divide.
In their investigation of melanoma samples from mice, the researchers observed that immune cells migrated into the tumor tissue once the senescence process had been reactivated by drugs.
Senescence keeps cancer cells in hibernation
Together with programmed cell death, cellular senescence is one of the body's most important lines of defense against cancer. This protective mechanism epigenetically silences genes that regulate cell division. Methyltransferase enzymes mark histone proteins – the "spools" around which DNA is wrapped.
These marks deactivate the section of DNA that is next to the histone. Clemens Schmitt and his team investigated two different demethylase enzymes that can counteract this process. Their ability to "erase" these histone marks makes the enzymes crucial for controlling and disabling senescence.
Potential seen for combination therapies
Cellular senescence is an important and welcome avenue for cancer therapies due to its ability to prevent the further growth of tumors. But its functions are not limited to blocking cancer, as Schmitt's research team recently reported in the scientific journal Nature.
Clemens Schmitt believes the immigration of immune cells into the tumor that was observed in the senescence mechanism holds great potential for a new type of combination therapy.
These findings are particularly promising for the treatment of melanoma, as this cancer responds poorly to chemotherapy and is better combated with the help of new immunotherapies. Authors now want to see how well immunotherapy and senescence-inducing therapy can be combined in clinical trials.