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.

Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial‐mesenchymal transition and 5‐fluorouracil resistance

“…Activation of the Akt pathway can alleviate the tumor cell damage caused by chemotherapeutic drugs by enhancing DNA repair and inducing the expression of drug pump proteins . NFIB was reported to bind to the EZH2 promoter and promote EZH2 expression, which could activate the PI3K/AKT pathway . Wu et al discovered that NFIB can activate the Akt/Stat3 signaling pathway in gastric cancer.…”

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

“…BRN2 is another transcription factor increased in metastatic melanomas. Overexpressing BRN2 in melanoma cell lines causes NFIB to increase, but significantly decreases NFIC levels (as well as NFIA and NFIX) 75. The ChEA Transcription Factors database records that EZH2 interacts with NFIA, NFIC and NFIX, but not NFIB.…”

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

“…Cytotoxicity associated with chemo‐ and radiotherapy is much greater in proliferating populations, thus giving slow‐cycling cells a specific survival advantage against more general treatments. MITF low populations are also characterized to be intrinsically resistant to more specific therapies, particularly those defined by high AXL expression (Fane et al, ; Konieczkowski et al, ; Muller et al, ). Hypoxia also plays a prevalent role in the phenotype switching model of melanoma progression, as it has been shown to act as a central mediator of a HIF‐1α‐dependent switch from an ROR1‐positive proliferative cell state to an ROR2‐positive invasive cell state (O'Connell et al, ) .…”