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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Published in:Oncogenesis (New York, NY) NY), 2018-11, Vol.7 (11), p.91-15, Article 91
Main Authors: 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
Format: Article
Language:English
Subjects:
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Apoptosis
Breast cancer
Cell Biology
Chromatin
Clonal deletion
CRISPR
Ets-1 protein
Gene expression
Gene regulation
Human Genetics
Internal Medicine
Invasiveness
Medicine
Medicine & Public Health
Metastases
Metastasis
Oncology
RelA protein
Therapeutic applications
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Summary: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.
ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-018-0101-3