O-Glcnac Transferase Inhibition In Breast Cancer Cells

O-linked-N-acetylglucosamination (O-GlcNAcylation) is a post-translational modification that occurs on serine and threonine amino acid residues of the intracellular proteins. O-GlcNAcylation of numerous targets is catalyzed by a single enzyme - O-GlcNAc-transferase (OGT). O-GlcNAcylation impacts protein activation and stability thereby regulating several key biological functions, and is heavily involved in cancer development and progression. OGT expression and total protein O-GlcNAcylation are elevated in many cancers compared to non-malignant adjacent tissues. In breast cancer, this increase also has a positive correlation with the tumor grade suggesting a possible link to metastasis and disease progression. Here we investigated the effects of OGT inhibition in two triple-negative (TNBC) and two receptor-positive luminal breast cancer cell lines. Treatment of cells with an OGT inhibitor as well as OGT knockdown led to a strong decrease in viability and proliferation of the TNBC cells, but significantly less so in the luminal receptor-positive cell lines. This differential response was evaluated using analysis of apoptosis, cell cycle, gene expression and a reverse-phase antibody-based protein array (RPPA). We found that cell cycle progression was affected by OGT inhibition. In addition, proteomics data pointed towards the transcription factor hairy and enhancer of split-1 (HES1) as a possible mediator of the cytotoxicity observed in the TNBC cell lines. We currently work to elucidate the molecular mechanisms of HES1 regulation by OGT and its effect on TNBC cell survival and apoptosis. In conclusion, OGT inhibition has a pronounced cytotoxic effect on the TNBC cells and may have some potential for therapeutic use in the future. Citation Format: Anna Barkovskaya, Lina Prasmickaite, Damien Y. Duveau, Ian G. Mills, Gunhild M. Maelandsmo, Siver A. Moestue, Harri M. Itkonen. O-GlcNAc transferase inhibition in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1131. doi:10.1158/1538-7445.AM2017-1131