NFIB Mediates BRN2 Driven Melanoma Cell Migration and Invasion Through Regulation of EZH2 and MITF
Mitchell E. Fane,
Yash Chhabra,
David E.J. Hollingsworth,
Jacinta L. Simmons,
Loredana Spoerri,
Tae Gyu Oh,
Jagat Chauhan,
Toby Chin,
Lachlan Harris,
Tracey J. Harvey,
George E.O. Muscat,
Colin R. Goding,
Richard A Sturm,
Nikolas K. Haass,
Glen M. Boyle,
Michael Piper,
Aaron G. Smith
Affiliations
Mitchell E. Fane
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Yash Chhabra
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
David E.J. Hollingsworth
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Jacinta L. Simmons
Cancer Drug Mechanisms Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
Loredana Spoerri
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
Tae Gyu Oh
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
Jagat Chauhan
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK
Toby Chin
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Lachlan Harris
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Tracey J. Harvey
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
George E.O. Muscat
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
Colin R. Goding
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK
Richard A Sturm
Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, QLD 4102, Australia
Nikolas K. Haass
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
Glen M. Boyle
Cancer Drug Mechanisms Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
Michael Piper
The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Aaron G. Smith
School of Biomedical Sciences, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba, QLD 4102, Australia
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.
