Cells, like people, are meant to grow old and die. The fact that cancer cells are able to break this rule, avoiding the period of decline known as senescence, could have something to do with epigenetics. Researchers at the LBMCC lab in Luxembourg have revealed for the first time the mechanisms that may underlie this trick in chronic myeloid leukemia, suggesting routes toward new therapies promoting senescence and the end of life for cancer cells.
Telomeres visible in red at the ends of chromosomes
(By Reinhard Stindl (Own work) [CC-BY-SA-3.0], via Wikimedia Commons)
After a busy and active youth, cells, like the humans they make up, eventually enter a quieter period of decline. They stop dividing and, in the end, may die. Researchers have been studying this phase, called senescence, to see if it could be triggered in cancer cells as a new therapeutic approach. Working in chronic myeoloid leukemia cells, Dr. Marc Diederich’s team at the LBMCC (Laboratoire de Biologie Moléculaire et Cellulaire du Cancer) in Luxembourg recently showed what was going on at the DNA level as cells became senescent – the first step towards being able to control this process in cancer.
Cells approaching the end of their life show specific physical features like larger size, a flattened shape, and a whole lot of compartments, called vacuoles, in the cytoplasm. They also have shortened telomeres, which are like caps on the ends of chromosomes that get worn down a little every time a cell divides. This erosion of telomeres over time seems to play a role in the cellular aging process itself. Cancer cells, however, pay no attention to the rules. They use an enzyme called telomerase to rebuild and maintain their telomeres, avoiding both senescence and death.
Senescence can be triggered prematurely in cells by stressing them out – with toxic drugs, for instance – and perhaps also by shortening telomeres beyond a critical point. Dr. Diederich’s team set out to investigate what was controlling the activity of cancer cells’ telomerase, allowing them to get around their fate. Knowing this could help researchers understand how to block it, and reactivate the program for a normal cellular end of life.
The answer may have something to do with epigenetics. This refers to the switching on or off of genes by factors that do not affect the genetic sequence itself. For instance, the attachment of methyl groups (CH3) to the DNA prevents genes from being transcribed. Past studies had shown that some cancers are likely caused by the epigenetic switching off of genes that would normally block tumor development. There is also evidence that methylation is involved in senescence—or the ability to escape it. Indeed, the LBMCC team confirmed that leukemia cells treated with an agent promoting DNA demethylation (2'-deoxy-5-azacytidine, or DAC), could be pushed into a state of senescence.
The researchers explored the details further. The DAC treatment corresponded closely to effects they saw in telomeres and telomerase. The chromosome caps in these cells were shorter than in untreated cancer cells and the telomerase was less active—more like normal cells, on both points. Could this mean that DNA methylation is involved in cancer cells’ production of telomerase, allowing them to avoid senescence and death?
The researchers traced the process backward, step by step. The level of telomerase activity depended on the amount of a molecule called hTERT, which serves as the enzyme’s catalyst. And hTERT, they found, was expressed less in cells treated with DAC.
Taking one more step back, the Luxembourg team looked at an element that is key in getting hTERT transcribed: the protein c-myc. When c-myc binds to the promoter of the hTERT gene, more of the latter is produced. The effect of DAC treatment here? DAC led to less c-myc binding to its target. Thus, less hTERT was produced to maintain telomere length. The presence of the demethylating DAC resulted in decreased telomerase activity, and led to the leukemia cells drifting off into senescence and, finally, cell death.
This work by the team at the LBMCC is the first to offer a step-by-step explanation for precisely how DAC, currently in trials for leukemia treatment, has its effect. Since senescent cells may be removed by the immune system, this seems to be a natural mechanism for bringing cancer to a halt while still in its early stages. Therapies actively promoting senescence could, therefore, prove a promising new path for cancer treatment.
For more information about this study, see the original publication, available on MyScienceWork, and connect with the authors by visiting their profiles on the LBMCC platform: