title: Modulation of Brahma expression by the mitogen-activated protein kinase/extracellular signal regulated kinase pathway is associated with changes in melanoma proliferation.
abstract: Brahma (BRM) and Brahma-related gene 1(BRG1) are catalytic subunits of SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes. BRM is epigenetically silenced in a wide-range of tumors. Mutations in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene occur frequently in melanoma and lead to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK1/2) pathway. We tested the hypothesis that BRM expression is modulated by oncogenic BRAF and phosphorylation of ERK1/2 in melanocytes and melanoma cells. Expression of oncogenic BRAF in melanocytes and melanoma cells that are wild-type for BRAF decreased BRM expression and increased BRG1 expression. Inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) or selective inhibition of BRAF in melanoma cells that harbor oncogenic BRAF increased BRM expression and decreased BRG1 expression. Increased BRM expression was associated with increased histone acetylation on the BRM promoter. Over-expression of BRM in melanoma cells that harbor oncogenic BRAF promoted changes in cell cycle progression and apoptosis consistent with a tumor suppressive role. Upon inhibition of BRAF(V600E) with PLX4032, BRM promoted survival. PLX4032 induced changes in BRM function were correlated with increased acetylation of the BRM protein. This study provides insights into the epigenetic consequences of inhibiting oncogenic BRAF in melanoma through modulation of SWI/SNF subunit expression and function.
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States.
authors.forename: Aanchal
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States.
authors.forename: Srinivas Vinod
authors.initials: SV
authors.lastname: Saladi
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States.
authors.forename: Archit R
authors.initials: AR
authors.lastname: Trivedi
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States.
authors.forename: Shweta
authors.initials: S
authors.lastname: Aras
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States.
authors.forename: Huiling
authors.initials: H
authors.lastname: Qi
authors.affiliation: University of Wisconsin, Department of Dermatology, 1300 University Avenue, #439, Madison, WI 53706, United States.
authors.forename: Ashika
authors.initials: A
authors.lastname: Jayanthy
authors.affiliation: University of Wisconsin, Department of Dermatology, 1300 University Avenue, #439, Madison, WI 53706, United States.
authors.forename: Vijayasaradhi
authors.initials: V
authors.lastname: Setaluri
authors.affiliation: University of Toledo College of Medicine, Department of Biochemistry and Cancer Biology, 3035 Arlington Ave, Toledo, OH 43614, United States. Electronic address: ivana.delaserna@utoledo.edu.
authors.forename: Ivana L
authors.initials: IL
authors.lastname: de la Serna
mesh_terms: D019943:Amino Acid Substitution; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: BRAF(V600E); BRG1/BRM; Melanoma; Mitogen-activated protein kinase/extracellular signal regulated
                      kinase (ERK1/2) pathway; SWI/SNF chromatin remodeling enzymes; Vemurafenib