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

ABSTRACT: 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-?Bs. 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.

SUBMITTER: Kim GC

PROVIDER: S-EPMC6250664 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Kim Gi-Cheon GC Kwon Ho-Keun HK Lee Choong-Gu CG Verma Ravi R Rudra Dipayan D Kim Taemook T Kang Keunsoo K Nam Jong Hee JH Kim Young Y Im Sin-Hyeog SH

Oncogenesis 20181123 11

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 regio ...[more]

PMID: 30467308

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Project description:BackgroundCore fucosylation (addition of fucose in α-1,6-linkage to core N-acetylglucosamine of N-glycans) catalyzed by fucosyltransferase 8 (FUT8) is critical for signaling receptors involved in many physiological and pathological processes such as cell growth, adhesion, and tumor metastasis. Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) regulates the invasion and metastasis of breast tumors. However, whether receptor core fucosylation affects TGF-β signaling during breast cancer progression remains largely unknown.MethodIn this study, gene expression profiling and western blot were used to validate the EMT-associated expression of FUT8. Lentivirus-mediated gain-of-function study, short hairpin RNA (shRNA) or CRISPR/Cas9-mediated loss-of-function studies and pharmacological inhibition of FUT8 were used to elucidate the molecular function of FUT8 during TGF-β-induced EMT in breast carcinoma cells. In addition, lectin blot, luciferase assay, and in vitro ligand binding assay were employed to demonstrate the involvement of FUT8 in the TGF-β1 signaling pathway. The role of FUT8 in breast cancer migration, invasion, and metastasis was confirmed using an in vitro transwell assay and mammary fat pad xenograft in vivo tumor model.ResultsGene expression profiling analysis revealed that FUT8 is upregulated in TGF-β-induced EMT; the process was associated with the migratory and invasive abilities of several breast carcinoma cell lines. Gain-of-function and loss-of-function studies demonstrated that FUT8 overexpression stimulated the EMT process, whereas FUT8 knockdown suppressed the invasiveness of highly aggressive breast carcinoma cells. Furthermore, TGF-β receptor complexes might be core fucosylated by FUT8 to facilitate TGF-β binding and enhance downstream signaling. Importantly, FUT8 inhibition suppressed the invasive ability of highly metastatic breast cancer cells and impaired their lung metastasis.ConclusionsOur results reveal a positive feedback mechanism of FUT8-mediated receptor core fucosylation that promotes TGF-β signaling and EMT, thus stimulating breast cancer cell invasion and metastasis.

Dataset Information

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

Publications

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

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