GREB1: An evolutionarily conserved protein with a glycosyltransferase domain links ERalpha glycosylation and stability to cancer

Menée à l'aide notamment de lignées cellulaires de cancer du sein et d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'enzyme GREB1 stabilise les récepteurs ER alpha des cellules cancéreuses et démontre une association entre l'expression de cette enzyme et la réponse tumorale au tamoxifène

Résumé en anglais

What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher GREB1 expression in ERα+ve breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.