Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Barkovskaya, Anna, Seip, Kotryna, Hilmarsdottir, Bylgja, Maelandsmo, Gunhild M., Moestue, Siver A., Itkonen, Harri M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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
_version_ 1783409087067717632
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
work_keys_str_mv AT barkovskayaanna oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes
AT seipkotryna oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes
AT hilmarsdottirbylgja oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes
AT maelandsmogunhildm oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes
AT moestuesivera oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes
AT itkonenharrim oglcnactransferaseinhibitiondifferentiallyaffectsbreastcancersubtypes