Abstract |
Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of the BRMS1 gene contributes to epithelial-to-mesenchymal transition (EMT). Using a short hairpin RNA (shRNA) system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressing BRMS1 shRNAs (BRMS1 knockdown [BRMS1(KD)]) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed in BRMS1(KD) cells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor kappa B (NF-κB). In addition, chromatin immunoprecipitation analysis demonstrates that loss of BRMS1 increases Twist1 promoter occupancy of RelA/p65 K310-a key histone modification associated with increased transcription. Knockdown of Twist1 results in reversal of BRMS1(KD)-mediated EMT phenotypic changes. Moreover, in our animal model, BRMS1(KD)/Twist1(KD) double knockdown cells were less efficient in establishing lung tumors than BRMS1(KD) cells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-κB-dependent regulation of Twist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.
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Authors | Yuan Liu, Marty W Mayo, Aizhen Xiao, Emily H Hall, Elianna B Amin, Kyuichi Kadota, Prasad S Adusumilli, David R Jones |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 35
Issue 1
Pg. 303-17
(Jan 2015)
ISSN: 1098-5549 [Electronic] United States |
PMID | 25368381
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015, American Society for Microbiology. All Rights Reserved. |
Chemical References |
- BRMS1 protein, human
- Histones
- NF-kappa B p50 Subunit
- NFKB1 protein, human
- Nuclear Proteins
- RNA, Small Interfering
- Repressor Proteins
- TWIST1 protein, human
- Transforming Growth Factor beta
- Twist-Related Protein 1
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Topics |
- Animals
- Carcinoma, Non-Small-Cell Lung
(metabolism)
- Cell Line, Tumor
- Cell Survival
- Epithelial-Mesenchymal Transition
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Histones
(metabolism)
- Humans
- Lung Neoplasms
(metabolism)
- Lymphatic Metastasis
- Mice
- Mice, Nude
- NF-kappa B p50 Subunit
(metabolism)
- Neoplasm Metastasis
- Neoplasm Transplantation
- Nuclear Proteins
(genetics, metabolism)
- Phenotype
- RNA, Small Interfering
(metabolism)
- Repressor Proteins
(genetics, metabolism)
- Transforming Growth Factor beta
(metabolism)
- Twist-Related Protein 1
(genetics, metabolism)
- Wound Healing
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