Despite a clear oncogenic role

Despite a clear oncogenic role for NFIB in SCLC and melanoma, tumour suppressive functions have been demonstrated or strongly suggested in other cancers. Although the molecular mechanisms behind its anti-oncogenic functions are not well understood, the fact that NFIB is widely expressed in multiple normal tissues and cell types, supports a potential role in the maintenance of cellular homeostasis, and conceivably as a barrier to malignant transformation. Accordingly, we and others have shown that downregulation of NFIB leads to the activation of less differentiated tumour phenotypes, culminating in increased cancer aggressiveness and ultimately poorer patient survival. The concept that purchase SCH527123 undergo a process of dedifferentiation to a more progenitor like state frequently associated with metastasis, has been documented in various cancer models (Friedmann-Morvinski and Verma, 2014). Moreover, NFIB appears to play a critical role in maintaining stem cell quiescence in some adult tissues (Harris et al., 2015; Chang et al., 2013; Rolando et al., 2016). Further supporting a link between NFIB and the modulation of cellular fate, this NFI member has been shown to be regulated/interact with two key pluripotent transcription factors, MYC and SOX2, respectively (Mollaoglu et al., 2016; Engelen et al., 2011). Although cancer-related studies have focused mostly on cell-intrinsic changes caused by NFIB, it is worth noting that tumour microenvironment changes might also contribute to drive NFIB-induced cancer aggressiveness. Supporting this hypothesis, NFIB has been shown to regulate endothelins – secreted factors with the ability to mediate intercellular crosstalk – which can promote tumour angiogenesis, migration and invasion (Chang et al., 2013; Rosano et al., 2013). Corroborating a potential role in the tumour microenvironment, NFIB also appears to be expressed in the stroma surrounding tumours (Grabowska et al., 2016; unpublished observations). Major questions that remain to be answered pertain to the understanding of how NFIB\'s diverse functions – which promote cell differentiation during late stages of development in a range of tissues, and regulate the maintenance of populations of stem cells in adult tissues – contribute to its significant and paradoxical roles in tumourigenesis. Some specific questions that need to be addressed are: 1) What are the important upstream regulators of NFIB in different cancer-related contexts? 2) Do the many alternatively-spliced isoforms of NFIB play cooperative, or perhaps antagonist, roles during tumourigenesis? 3) What factors might mediate stabilization or enhanced degradation of NFIB transcripts in tumours? 4) How does the expression of NFIB binding partners, including other NFI family members and other transcription factors, influence its activity in cancer? Lastly, 5) What are the direct downstream targets of NFIB in different tumour types and stages, and are they the same or different from those identified during normal development and maintenance of tissue homeostasis? The development of quantitative pull-down assays with NFIB partner proteins and in vivo FRET measurements of NFI-partner protein interactions, combined with ChIP-seq, ATAC-seq, single cell RNA-seq and the use of conditional knock-out alleles of NFIB and other NFI family members, should allow us to answer these important questions. In closing, the paradoxical involvement of NFIB in both the inhibition and promotion of tumour development and progression in different malignancies; especially between different tumour subtypes within a single organ system, such as in lung, brain and skin, corroborates its diverse and distinct roles in specific tissues and cell types. This follows from the fact that NFI-mediated transcriptional activation or repression of specific gene promoters, varies depending on cell type and upon details of the cellular context (Chaudhry et al., 1998; Chaudhry et al., 1999), resulting in the modulation of the expression of a plethora of diverse tissue-specific genes (Gronostajski, 2000). Consequently, caution must be exercised in the development of any future therapies aimed to manipulate NFIB levels – which may result in unexpected/undesired effects, with the potential for exacerbation of tumour aggressiveness. Further insights into the fascinating role of this enigmatic transcription factor in cancer will certainly open new doors to clinical translation of these findings.