One of the secrets behind the success of cancer cells is their ability to proliferate indefinitely by keeping long telomeres. In healthy cells, these sections of the genome located at the end of chromosomes shorten during each cellular division. When these telomeres become too short, the cell stops proliferating and enters into the state of senescence. Researchers at the University of Liège have discovered an enzyme that allows cancer cells to maintain the length of their telomeres. The inhibition of this enzyme affects telomeric structures and makes those cells much more sensitive to chemotherapeutic drugs.

In eukaryotic cell, the DNA is not a ‘naked” molecule but it goes through several levels of condensation to form chromatin; the chromosome being the most compact form of DNA. In order to reach this highest level of condensation, the DNA wraps around the histone proteins just like thread around a bobbin. This structure offers the genome a certain amount of stability, particularly during cellular division, but DNA cannot be transcribed in this form. For genomic sequences to be transcribed into RNA and then translated into protein, the DNA must first become more "flexible", less condensed, in order to be read. This is where histone deacetylases (HDAC) come in.  "The function of this family of 18 enzymes is to open and close the DNA molecule by modifying the chromatin's structure," explains Denis Mottet, FRS-FNRS Research Associate at the Metastasis Research Laboratory, GIGA-Cancer, ULg. As a cancer specialist, he studies histone deacetylases because they are overrepresented in cancer tissues. "We are trying to understand their potential role in different biological processes related to cancer growth, since these enzymes appear to be promising therapeutic targets." 

Telomeres and cellular ageing

Denis Mottet and his colleagues began their research on HDAC by inhibiting their activities using pharmacological molecules that could inhibit all 18 members of the family. "But these enzymes are also present in healthy cells and are necessary for several physiological processes. To avoid creating side-effects and to target certain HDAC more specifically, we worked to determine which members of this enzyme family played the most important role in cancer cells," the scientist continues. Thus for the past decade or so, Denis Mottet has been selectively inhibiting the expression of each of these HDAC members and observing the consequences of these manipulations on cell cultures. "We noticed that when we selectively inhibited histone deacetylase 5 (HDAC5), there was a reduction in proliferation and the cancer cells died," reveals Denis Mottet. "These results suggest that HDAC5 may be a promising therapeutic target, but we still don't fully understand the underlying mechanisms.”