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O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes
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 ex...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450885/ https://www.ncbi.nlm.nih.gov/pubmed/30952976 http://dx.doi.org/10.1038/s41598-019-42153-6 |
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author | Barkovskaya, Anna Seip, Kotryna Hilmarsdottir, Bylgja Maelandsmo, Gunhild M. Moestue, Siver A. Itkonen, Harri M. |
author_facet | Barkovskaya, Anna Seip, Kotryna Hilmarsdottir, Bylgja Maelandsmo, Gunhild M. Moestue, Siver A. Itkonen, Harri M. |
author_sort | Barkovskaya, Anna |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6450885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64508852019-04-10 O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes Barkovskaya, Anna Seip, Kotryna Hilmarsdottir, Bylgja Maelandsmo, Gunhild M. Moestue, Siver A. Itkonen, Harri M. Sci Rep Article 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. Nature Publishing Group UK 2019-04-05 /pmc/articles/PMC6450885/ /pubmed/30952976 http://dx.doi.org/10.1038/s41598-019-42153-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Barkovskaya, Anna Seip, Kotryna Hilmarsdottir, Bylgja Maelandsmo, Gunhild M. Moestue, Siver A. Itkonen, Harri M. O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title | O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title_full | O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title_fullStr | O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title_full_unstemmed | O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title_short | O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes |
title_sort | o-glcnac transferase inhibition differentially affects breast cancer subtypes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450885/ https://www.ncbi.nlm.nih.gov/pubmed/30952976 http://dx.doi.org/10.1038/s41598-019-42153-6 |
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