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Loss of BRMS1 promotes a mesenchymal phenotype through NF-κB-dependent regulation of Twist1.

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.
AuthorsYuan Liu, Marty W Mayo, Aizhen Xiao, Emily H Hall, Elianna B Amin, Kyuichi Kadota, Prasad S Adusumilli, David R Jones
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 1 Pg. 303-17 (Jan 2015) ISSN: 1098-5549 [Electronic] United States
PMID25368381 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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