NFIB mediates BRN2 driven melanoma cell migration and invasion through regulation of EZH2 and MITF
| Autor: | Richard A. Sturm, Colin R. Goding, Nikolas K. Haass, Jagat Chauhan, David E.J. Hollingsworth, Mitchell Fane, Jacinta L. Simmons, Lachlan Harris, Loredana Spoerri, Tae Gyu Oh, Michael Piper, Glen M. Boyle, Yash Chhabra, George E.O. Muscat, Toby Chin, Tracey J. Harvey, Aaron G. Smith |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Blotting Western Transplantation Heterologous Phenotypic switching lcsh:Medicine Biology BRN2 General Biochemistry Genetics and Molecular Biology Metastasis 03 medical and health sciences Invasion Cell Movement Cell Line Tumor medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Neoplasm Invasiveness Epigenetics Melanoma Transcription factor Homeodomain Proteins Mice Knockout Mice Inbred BALB C Microphthalmia-Associated Transcription Factor lcsh:R5-920 Reverse Transcriptase Polymerase Chain Reaction lcsh:R EZH2 Epigenetic Cell migration General Medicine NFIB Microphthalmia-associated transcription factor medicine.disease Gene Expression Regulation Neoplastic NFI Transcription Factors 030104 developmental biology Microscopy Fluorescence POU Domain Factors Cancer research lcsh:Medicine (General) Research Paper Protein Binding |
| Zdroj: | EBioMedicine, Vol 16, Iss C, Pp 63-75 (2017) EBioMedicine |
| DOI: | 10.1016/j.ebiom.2017.01.013 |
| Popis: | 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. Highlights • NFIB mediates a slow cycling, highly invasive/migratory melanoma cell phenotype downstream of BRN2. • NFIB increases EZH2 expression downstream of BRN2, which further decreases MITF levels. • NFIB expression is defined by an invasive gene signature and colocalises with BRN2 in primary and metastatic human melanoma tumours. Melanoma is a heterogeneous cancer, made up of many cellular populations that differ in their ability to induce tumour growth or invasion throughout the body (metastasis). These populations have been found to switch back and forth to drive invasion and progression. This process appears to be controlled by an inverse axis between two genes, MITF and BRN2. BRN2 drives metastatic spread, but the process by which it acts is not well characterized and cannot be targeted clinically. This study has uncovered a role for the gene NFIB in driving invasion downstream of BRN2. Importantly, it appears to drive this process through EZH2, which can be targeted therapeutically to reduce metastasis. |
| Databáze: | OpenAIRE |
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