The work in our lab is dedicated to the study of the molecular and cellular mechanisms involved in the development of human cancers with a particular emphasis on the role of certain post-translational modifications. Two distinct but complementary approaches are taken: a first, 'global' approach seeks to establish a general profile of genetic, epigenetic or post-transcriptional alterations associated with hepatocellular carcinoma (HCC), whereas the second, more 'mechanistic' approach, centers on the role of the SUMO pathway in both development and oncogenesis.

Genetics and epigenetic of primary liver cancer

To better understand the mechanisms underlying liver cancer, we wish to establish a global profile of genetic and post-genetic alterations associated with this tumor type. To this aim : (i) mutational and functional analyses have been conducted for candidate tumor suppressor genes on chromosomes 8p et 4q. (ii) we studied general and specific profiles of chromatin modifications, both at the histone and DNA levels, as well as the effects of deacetylase inhibitors (HDACi) in HCC cell lines. (iii) we initiated a comprehensive characterization of the main actors of epigenetic regulation (modifying/de-modifying enzymes, modifiers themselves, histone variants and mi-RNAs) in HCC.

Role of the SUMO pathway

The second major research axis is devoted to the study of the post-translational modification by the ubiquitin-like SUMO protein, now known to play critical roles in several fundamental cellular processes. Two specific, complementary approaches were taken. The first aimed at identifying novel enzymes associated with this pathway as well as new substrates. We described two new SUMO targets, PARP1 and Ataxin-7, and identified FIP200 as an important co-regulator of the SUMO E3 ligase PIASy. The second was devoted to study the role of sumoylation in animal development and in oncogenesis. We inactivated in mice the Ubc9 gene which encodes the unique E2 enzyme. Loss of sumoylation results in early embryonic lethality associated with severe defects in nuclear architecture and function (Figure).

In parallel, we described a major role for PIASy in telomere maintenance and cellular senescence. Finally, we described a physical and functional interaction between PML, a major SUMO susbtrate, and the MAR-associated protein SATB1 in regulating chromatin loop architecture.