Advancing Epigenetics Towards Systems Biology

How, in some cancers, a protein excess could induce treatments resistance

A collaboration between EpiGeneSys members, the Almouzni's and Imhof's teams, led to the discovery of a cellular mechanism that could explain the resistance of certain cancers to specific treatments (Mol Cell. 2014 Feb 20;53(4):631-44).

In Geneviève Almouzni's lab, Nicolas Lacoste, biochemist, and Adam Woolfe, bioinformatician, studied CenH3, the histone variant found specifically at the centromere. Their first analysis revealed a CenH3 overexpression in 50% of cancers, and particularly in the most aggressive ones. Then, a high-resolution map of this variant in a CenH3 overexpressing cell line was obtained showing that CenH3 was accumulating not only at the centromeres but along chromosomes' arms as well.

With the help of Axel Imhof and Hitoshi Kurumizak's groups, they further studied these cells and revealed a controled ectopic localisation of CenH3 and surprisingly, a resistance to cancer treatments generating DNA breaks. These observations led to a new hypothesis to explain cancer resistance to certain treatments: CenH3 ectopic localisation results in alternative sites of centromere formation rescuing pieces of broken DNA. Indeed, instead of being lost during cell division, these "micro" chromosomes will behave like normal ones. Therefore these cancer cells will keep intact their gene pool and will be able to continue to divide and survive.

The authors are currently testing this hypothesis.