Nuclear Factor I/B: A Master Regulator of Cell Differentiation with Paradoxical Roles in Cancer

Abstract

Emerging evidence indicates that nuclear factor I/B (NFIB), a transcription factor required for proper development and regulation of cellular differentiation in several tissues, also plays critical roles in cancer. Despite being a metastatic driver in small cell lung cancer and melanoma, it has become apparent that NFIB also exhibits tumour suppressive functions in many malignancies. The contradictory contributions of NFIB to both the inhibition and promotion of tumour development and progression, corroborates its diverse and context-dependent roles in many tissues and cell types. Considering the frequent involvement of NFIB in cancer, a better understanding of its multifaceted nature may ultimately benefit the development of novel strategies for the management of a broad spectrum of malignancies. Here we discuss recent findings which bring to light NFIB as a crucial and paradoxical player in cancer.

Keywords: Cancer; Cellular differentiation; Developmental transcription factor; NFIB; Oncogene; Tumour suppressor.

Fig. 1

NFIB expression overview in human tissues. NFIB is expressed in a range of tissues. RNA-sequencing data from 31 tissues generated by the Genotype-Tissue Expression Project (GTEx; https://www.gtexportal.org/) are reported as median RPKM (Reads Per Kilobase of transcript per Million mapped reads). Colour-coding is based on 13 tissue groups, each consisting of tissues with common functional features (adapted from the Human Protein Atlas: http://www.proteinatlas.org/ENSG00000147862-NFIB/tissue, available from v16.1.proteinatlas.org).

Fig. 2

NFIB functions in development and physiology. NFIB is required for the development of the lung, brain and submandibular glands. It is also required for the maintenance of a range of physiological processes in several tissues, including adipocyte differentiation, megakaryocyte maturation, regulation of androgen receptor signaling in the prostate, and epithelial-melanocyte stem cell behaviour in the hair follicle niche. Note: Experiments assessing the diverse functions of NFIB were performed mainly using mouse models, and in some cases human cell lines.

Fig. 3

Paradoxical roles of NFIB in cancer. NFIB has shown both oncogenic and tumour suppressive functions in different cancer types and subtypes.

Fig. 4

NFIB activity is regulated at multiple levels. A) Cell-type and context-specific transcription of NFIB in various tissues is regulated by multiple transcription factors including ASCL1, MYC, PAX6 and BRN2. B) At least 20 alternatively-spliced isoforms of NFIB have been identified. C & D) Drosha has been shown to destabilize NFIB nuclear transcripts (C) and miRNAs, such as, miR-92b-3p, miR-21 and miR-365 have been shown to affect cytosolic NFIB transcript stability (D). E) NFIB protein products of alternatively-spliced transcripts can form homo- and hetero-dimers with other NFI gene products. In addition, NFIB activity can also be influenced by its binding to other nuclear regulatory proteins (NRPs), and by post-translational modifications (not shown). F) NFIB regulates the expression levels of multiple downstream targets in various tissues, including EZH2, SFTPC, IGFBP5, ELN and EDN2.