Nuclear factor I/B: Duality in action in cancer pathophysiology

The nuclear factor I (NFI) family of transcription factors plays a decisive role in organ development and maturation. Their deregulation has been linked with various diseases, most notably cancer. NFIB stands apart from the other NFI family members given its unique ability to drive both tumor suppressive and oncogenic programs. Thus, the ultimate impact of deregulated NFIB signaling is cancer-specific and strongly influenced by an intricate network of upstream regulators and downstream effectors. Deciphering the events that drive NFIB's paradoxical roles within these networks will enable us to not only understand how this critical transcription factor enacts its dual roles but also drive innovations to help us effectively target NFIB in different cancers. Here, we provide an in-depth review of NFIB. Starting with its defining role in the development of various organs, most notably the central nervous system, we highlight critical signaling pathways and the impact of deregulation on neoplastic transformation, contrasting it with the effect of silencing alone. We then provide examples of its dual roles in various cancers, identifying specific signaling networks associated with oncogenesis versus tumor suppression. We incorporate an example of a cancer type, osteosarcoma, wherein NFIB enacts its dual functions and explore which pathways influence each function. In this manner, we suggest plausible mechanisms for its role-switching from cancers sharing common triggering events in the setting of NFIB deregulation. We also review how NFIB enhances aggressiveness by driving metastasis, stemness, and chemoresistance. We conclude with a discussion on efficacious ways to target NFIB and pose some unanswered questions that may further help solidify our understanding of NFIB and facilitate clinical translation of NFIB targeting.