Fight against cancer affecting the packaging of DNA
Fighting cancer by inducing tumor cell death through the opening of the packaging which prevents the cellular response to DNA damage.
When a cell accumulates mutations in DNA often occur in the onset of cancer. It is originated by the activation of one or more oncogenes or mutated genes in the cell able to proliferate uncontrollably and then give rise to cancer.
Fortunately, our cells have mechanisms that can block the uncontrolled cell proliferation. One of these is senescence, a form of premature aging of cells.
This is a phenomenon that occurs in the presence of a considerable amount of damaged DNA. DNA damage usually causes cell death but senescent cells, following the activation of an oncogene, “hide” this damage effectively through a very dense compaction of chromatin, the “packaging” of DNA.
To date, the activation of this mechanism of chromatin compaction was considered synonymous with cell senescence, with the positive function of blocking the proliferation of cancer cells.
The study conducted by Fabrizio dAdda di Fagagna, group leader of the research on telomeres and cellular senescence IFOM (FIRC Institute of Molecular Oncology) in Milan and published today in the prestigious journal Nature Cell Biology noted however that this mechanism is found unexpectedly in tumor cell proliferation in full. Their presence is therefore a survival mechanism for tumor cells because the signal attenuates the response to DNA damage.
“Acting on the ‘packaging’ of chromatin,” said the scientist “could therefore be the key to fighting cancer in which there is this cellular mechanism, opening of the promising therapeutic perspectives.”
The observation that cells expressing an oncogene are damaged but survived thanks to an excessive compaction of chromatin in fact led the team of scientists led by dAdda di Fagagna to try to “unpack” the chromatin in human cells by the administration in vitro therapeutic agents already used in oncology, inhibitors of HDAC. Since the use of this class of drugs appears to be specific for cells expressing an oncogene, the research team led by dAdda di Fagagna shows that the compaction of chromatin is not present only when it is in place a mechanism of cellular senescence but even in the middle of a cancer cell proliferation, and then turns out to be a phenomenon associated with a large number of tumors. “What we have seen,” said Gabriel Sullivan, one of the principal authors of the study is that cells treated with HDAC inhibitors were able to “hear” the damaged DNA and to raise the alarm response, bringing motion the mechanism of apoptosis, or programmed cell death. ” But not only: “surprisingly – added Raffaella Di Micco, the young co-author of the study, which is now continuing his research at New York University this only happens in those cells where there is an activated oncogene, sparing healthy cells “. Contrary to what happens in drug chemotherapy and radiotherapy, this treatment would act then to target only cancer cells without affecting the survival of normal cells whose DNA is damaged by an oncogene.
Many clinical trials have already provided for use of HDAC inhibitors as anticancer therapy, but currently only a fraction of patients respond to treatment. The extraordinary nature of the study is to have shown that cells can respond positively to the HDAC inhibitors will be those with the presence of high compaction of chromatin. “A very important result, which enables us to direct more accurately the current treatments for cancer tumors by selecting more suitable for treatment with this class of drugs,” said Saverio Minucci, head of research on chromatin alterations in tumorigenesis Department of Experimental Oncology of IEO and professor at the Department of Biomolecular Sciences and Biotechnology at the University of Milan, and HDAC expert who worked on the study for the identification of new molecular mechanism of action.
Research conducted by Fabrizio dAdda di Fagagna was made possible thanks to the main support, among others, the Italian Association for Cancer Research (AIRC) and the European Community.
