Lille 1 University, France
Agata Steenackers defended her PhD thesis in the field of Biology and Biotechnologies in November 2013 at the Lille 1 University (France). During her PhD, she developed a project around the expression of GD3 synthase and gangliosides in breast cancer cells lines. She is now on a post-doctoral position in Tony Lefebvre's team (UGSF) where she is studying the role of O-GlcNAcylation in colon cancer development.
The O-GlcNAc transferase (OGT) is a key regulator of the post-translational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) onto Ser/Thr residues. OGT uses the end product of the hexosamine biosynthetic pathway (HBP), UDP-GlcNAc, as a donor for O-GlcNAcylation processes. It is reported that OGT and O-GlcNAcylation levels are increased in cancers. We showed that in the colorectal cancers (CRC) cell lines (HT29, HCT116) the expression of OGT and O-GlcNAcylation level were elevated, and that O-GlcNAcylation directly interfered with β-catenin stability and proliferation of cells. Previous studies showed that oncogenic factors such as p53, MYC or β-catenin are O-GlcNAcylated. The Wnt/β-catenin pathway is modified in most CRC by genetic alteration of β-catenin or one member of the destruction complex. Consequently, β-catenin is protected from proteasomal degradation and therefore induces cell proliferation. A similar observation was made when HBP flux was increased by culturing cells in high glucose medium. In these conditions, -catenin was protected against the degradation thus accelerating cell proliferation. In a recent study, we identified four O-GlcNAcylation sites at the N-terminus of β-catenin, one of those (T41) localized in the destruction box is crucial for the control of β-catenin degradation. In that context we studied the effect of OGT silencing in CRC cell lines and non-cancer cell line CCD841CoN. We reported that silencing of OGT halved proliferative and migratory capacities of cancer cells. OGT knock-down also diminished cell adhesion corroborating previous observations that inhibiting O-GlcNAcylation decreases β-catenin/α-catenin interactions necessary for mucosa integrity, which suggests that O-GlcNAcylation also affects localization of -catenin at adherens junction level.
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