title: 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.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia, USA Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Xiao
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Hall
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Elianna B
authors.initials: EB
authors.lastname: Amin
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA jonesd2@mskcc.org.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C410024:BRMS1 protein, human; D006657:Histones; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C103173:TWIST1 protein, human; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1