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Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness

Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (Ets1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and...

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Autores principales: Kim, Gi-Cheon, Kwon, Ho-Keun, Lee, Choong-Gu, Verma, Ravi, Rudra, Dipayan, Kim, Taemook, Kang, Keunsoo, Nam, Jong Hee, Kim, Young, Im, Sin-Hyeog
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250664/
https://www.ncbi.nlm.nih.gov/pubmed/30467308
http://dx.doi.org/10.1038/s41389-018-0101-3
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author Kim, Gi-Cheon
Kwon, Ho-Keun
Lee, Choong-Gu
Verma, Ravi
Rudra, Dipayan
Kim, Taemook
Kang, Keunsoo
Nam, Jong Hee
Kim, Young
Im, Sin-Hyeog
author_facet Kim, Gi-Cheon
Kwon, Ho-Keun
Lee, Choong-Gu
Verma, Ravi
Rudra, Dipayan
Kim, Taemook
Kang, Keunsoo
Nam, Jong Hee
Kim, Young
Im, Sin-Hyeog
author_sort Kim, Gi-Cheon
collection PubMed
description Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (Ets1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of Ets1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the Ets1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate Ets1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with Ets1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in Ets1 expression, which led to alterations of Ets1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of Ets1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for Ets1-mediated metastatic breast cancer.
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spelling pubmed-62506642018-11-26 Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness Kim, Gi-Cheon Kwon, Ho-Keun Lee, Choong-Gu Verma, Ravi Rudra, Dipayan Kim, Taemook Kang, Keunsoo Nam, Jong Hee Kim, Young Im, Sin-Hyeog Oncogenesis Article Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (Ets1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of Ets1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the Ets1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate Ets1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with Ets1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in Ets1 expression, which led to alterations of Ets1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of Ets1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for Ets1-mediated metastatic breast cancer. Nature Publishing Group UK 2018-11-23 /pmc/articles/PMC6250664/ /pubmed/30467308 http://dx.doi.org/10.1038/s41389-018-0101-3 Text en © The Author(s) 2018 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
Kim, Gi-Cheon
Kwon, Ho-Keun
Lee, Choong-Gu
Verma, Ravi
Rudra, Dipayan
Kim, Taemook
Kang, Keunsoo
Nam, Jong Hee
Kim, Young
Im, Sin-Hyeog
Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title_full Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title_fullStr Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title_full_unstemmed Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title_short Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness
title_sort upregulation of ets1 expression by nfatc2 and nfkb1/rela promotes breast cancer cell invasiveness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250664/
https://www.ncbi.nlm.nih.gov/pubmed/30467308
http://dx.doi.org/10.1038/s41389-018-0101-3
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