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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.

Original publication

DOI

10.1016/j.ebiom.2017.01.013

Type

Journal article

Journal

EBioMedicine

Publication Date

02/2017

Volume

16

Pages

63 - 75

Keywords

BRN2, Epigenetic, Invasion, Melanoma, Metastasis, NFIB, Animals, Blotting, Western, Cell Line, Tumor, Cell Movement, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Male, Melanoma, Mice, Inbred BALB C, Mice, Knockout, Microphthalmia-Associated Transcription Factor, Microscopy, Fluorescence, NFI Transcription Factors, Neoplasm Invasiveness, POU Domain Factors, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous