Abstract
Post-translational modification of intracellular proteins with a single N-acetylglucosamine sugar (O-GlcNAcylation) regulates signaling, proliferation, metabolism and protein stability. In breast cancer, expression of the enzyme that catalyzes O-GlcNAcylation – O-GlcNAc-transferase (OGT), and the extent of protein O-GlcNAcylation, are upregulated in tumor tissue, and correlate with cancer progression. Here we compare the significance of O-GlcNAcylation in a panel of breast cancer cells of different phenotypes. We find a greater dependency on OGT among triple-negative breast cancer (TNBC) cell lines, which respond to OGT inhibition by undergoing cell cycle arrest and apoptosis. Searching for the cause of this response, we evaluate the changes in the proteome that occur after OGT inhibition or knock-down, employing a reverse-phase protein array (RPPA). We identify transcriptional repressor - hairy and enhancer of split-1 (HES1) - as a mediator of the OGT inhibition response in the TNBC cells. Inhibition of OGT as well as the loss of HES1 results in potent cytotoxicity and apoptosis. The study raises a possibility of using OGT inhibition to potentiate DNA damage in the TNBC cells.
Highlights
IntroductionAn increase of the total O-GlcNAc levels, achieved through inhibition of OGA, can protect breast cancer cells from ER inhibitors[23]
We found that OGT inhibition or knock-down is significantly more toxic to triple-negative breast cancer (TNBC) cells than to the hormone receptor-positive cells (Fig. 1C)
While it is possible to sensitize receptor-positive cells to OGT inhibition by co-targeting either ER or PR, the combined effect of hormone receptor and OGT inhibition falls short of the prominent cyto-toxicity observed in the TNBC cells
Summary
An increase of the total O-GlcNAc levels, achieved through inhibition of OGA, can protect breast cancer cells from ER inhibitors[23]. It is not known if certain breast cancer subtypes are more dependent on protein O-GlcNAcylation or whether inhibition of OGT could be a useful therapeutic opportunity for some of the patients. In a panel of two receptor-positive and five TNBC cell lines, inhibition of OGT, either with a small-molecule inhibitor or through an siRNA-mediated knock-down, led to a more prominent cell death www.nature.com/scientificreports/. We identified a transcriptional repressor − hairy and enhancer of split-1 (HES1) as a protein selectively down-regulated in TNBC, but not in the receptor-positive cells in response to OGT inhibition. HES1 appears to have a specific role in TNBC cells, having a strong association with poor survival in this patient group
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