title: NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF.
abstract: While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis.
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD 4102, Australia.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Fane
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD 4102, Australia.
authors.forename: Yash
authors.initials: Y
authors.lastname: Chhabra
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: David E J
authors.initials: DEJ
authors.lastname: Hollingsworth
authors.affiliation: Cancer Drug Mechanisms Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: Jacinta L
authors.initials: JL
authors.lastname: Simmons
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Loredana
authors.initials: L
authors.lastname: Spoerri
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Oh
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Jagat
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: Chin
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Harris
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Harvey
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: George E O
authors.initials: GEO
authors.lastname: Muscat
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.affiliation: Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, QLD 4102, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Sturm
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.affiliation: Cancer Drug Mechanisms Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Piper
authors.affiliation: School of Biomedical Sciences, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD 4102, Australia; Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, QLD 4102, Australia. Electronic address: a260.smith@qut.edu.au.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Smith
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D050809:POU Domain Factors; C085076:transcription factor Brn-2; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: BRN2; Epigenetic; Invasion; Melanoma; Metastasis; NFIB