When the activity of individual genes it is longer required, there are two main mechanisms responsible for the “switching off”, mainly DNA methylation and the Polycomb protein complex.

Sometimes, these mechanisms lose their efficiency and some of the genes that should be “switched off” remain active. This, in turn, could lead to uncontrolled cellular proliferation, and tumorigenesis. These mechanisms, present both in lower organisms as well as in mammals, have always been thought to be separated and independent.

The work carried out by researchers of the Differentiation and Cancer Programme, at the Centre for Genomic Regulation (CRG), in Barcelona (Spain), demonstrates the cross-talk between these two gene silencing mechanisms in patients suffering from acute leukemia. The work, led by the ICREA researcher Luciano Di Croce, head of the group Epigenetics and Cancer, at the CRG, performed in collaboration with Kristian Helin’s group, at the Biotech Research and Innovation Centre in Copenhagen (Denmark), and Dr. Nomdedeu’s group, at the Santa Creu and Sant Pau Hospital, in Barcelona, will have important consequences in the development of new anti-tumor therapies.

On the one hand, the study shows a better understanding of the basic mechanisms of gene regulation and, on the other hand, identifies a possible new pathway to reactivate erroneously “switched off” genes in tumors. In 2002, in a study published in Science, Di Croce showed that uncontrolled DNA methylation contributed to tumor progression in its first stages. Less than a year ago, Di Croce’s group described, in another study published in Nature, the biochemical connection between the Polycomb protein complex and the enzymes methylating the DNA (DNA methyltransferases).

In this new study, Di Croce has shown that the two mechanisms are not only interconnected in leukemic cells, but also that one reinforces the other and, more importantly, that one needs the other.

Therefore - and this is one of the most interesting aspects of the investigation - if one of these mechanisms is blocked by specific drugs, the other will also be affected. The results achieved will allow, in the future, identifying new chemical compounds able to block both mechanisms simultaneously and exclusively, without altering other cellular mechanisms. For these reasons, this is one of the new investigations lines recently adopted by the group led by Di Croce.

Source: Villa R, Pasini D, Gutierrez A, Viré E, Nomdedeu JF, Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, and Di Croce L. “Role of the Polycomb repressive complex 2 in acute promyelocytic leucemia” Cancer Cell, June 2007