Mini-reviewThe convergent roles of the nuclear factor I transcription factors in development and cancer
Introduction
Cancer is driven by a series of acquired features that facilitate the initiation and progression of tumorigenesis by deregulating cellular proliferation and differentiation [1]. These features are acquired as a consequence of changes in gene expression, compromising physiological pathways that are normally regulated to ensure the function and maintenance of mature cellular phenotypes and optimal organ system performance. Not surprisingly, many pathways that are mis-regulated in cancer also function during normal development to control the rapid growth and development of each organ system [2]. Normal biological processes important for development, such as cellular proliferation, differentiation, and migration, are often compromised in cancer. As such, transcription factors that normally regulate these processes in development are often disrupted during tumorigenesis, either by direct mutation, or indirectly through chromosomal translocation. The pathways regulated by these transcription factors can be associated either with paediatric tumours during development or with adult cancers which result from mutations that revert mature cells to a developmental phenotype that enables rapid proliferation. In the last decade, genomic analyses and studies in mouse models have implicated such transcription factors in a variety of tumours across multiple organ systems.
The NFI, or CCAAT box-binding transcription factor (CTF), family of genes was first described for its role in stimulating the initiation of adenovirus DNA replication. It was later found to play important roles in transcriptional regulation, particularly during development [3]. The NFI family consists of four transcription factors in humans and most vertebrates: NFIA, NFIB, NFIC, and NFIX [4]. These share a highly conserved DNA-binding domain at their N-termini, and therefore bind to a common DNA sequence [5], [6] (Fig. 1). The C-termini of the NFI protein family demonstrate greater divergence, which is further compounded by the existence of multiple splice sites [7], [8], [9], [10], [11] and post-translational modifications [12], [13], [14], [15], [16]. Consequently, each NFI transcription factor encodes multiple splice variants, although the functions of many of these remain unknown.
NFI transcription factors regulate cell proliferation and differentiation during the development of multiple organ systems, including the central nervous system (CNS) [17], [18], [19], [20], [21], [22], [23], mammary gland [24], and lungs [18], [25] (Fig. 2). These transcription factors are also required to drive hematopoiesis [26], [27], [28], [29], [30], [31], osteoblastosis [32], [33], [34] and melanocytosis [35], [36] (Fig. 2). However, NFI deregulation can lead to uncontrolled cell proliferation or a failure to differentiate, and could therefore potentially contribute to tumour growth. In this review, we describe the oncogenic and tumour-suppressive potential of the NFI transcription factors and discuss what is known about the function of these genes in various types of cancer, in the context of their function in these same organ systems during development (Fig. 2).
Section snippets
Glioma
In astrocytomas, high expression levels of NFIA [37] and NFIB [38] correlate with better clinical outcome (Table 1). For example, a high level of NFIA mRNA in adult grade IV glioblastoma (GBM) and paediatric grade III-IV astrocytomas is associated with improved survival [37] (Table 1). Similarly, high NFIB expression correlates with better overall survival probability in GBM, grade II-IV astrocytomas, and gliomas in general [38] (Table 1). Higher-grade tumours are associated with lower NFIA [37]
Adenoid cystic carcinoma
The NFI transcription factors, particularly NFIB, appear to play a prominent role in various carcinomas, including adenoid cystic carcinoma (AdCC), breast carcinoma, and lung carcinoma (Table 3). In AdCC, MYB-NFIB fusion, or a similar fusion event affecting the MYB homologue, MYBL1, is found in 50% of tumours [67], [68], [69], [70], [71], [72], [73], [74], [75], [76] (Table 3). This frequent fusion event is regarded as a molecular hallmark of AdCC [70], [75], [77]. Interestingly, this event
Hematopoietic tumours
In the case of non-solid tumours, the NFI transcription factors have been implicated in hematopoietic tumours that include myeloproliferative neoplasms, leukemia, and lymphoma. Specifically, point mutations, focal deletions, and translocations of NFIA have been found in myeloproliferative neoplasms [114], [115] and acute erythroid leukemia [116] (Table 3). Loss of NFIB due to 9p LOH was also reported in approximately 30% of myeloproliferative neoplasms [117], [118], [119], and in T-cell
Other tumours
NFI transcription factors have also been implicated in other tumour types such as melanoma, osteosarcoma, neurofibroma, and benign tumours, although their role in these tumours is less clear. In human melanomas, genomic aberrations within the NFI genes, including single nucleotide polymorphism and translocations, have been observed [127], [128], [129] (Table 1, Table 3). Insertions within Nfia were also observed in tumours derived from an insertional mutagenesis melanoma mouse model [130] (
The context-dependent roles of NFI in cancer
Advances in high-throughput sequencing technologies have resulted in the identification of aberrations affecting NFI expression or function in various cancer types. Hence, there is now a body of evidence to suggest that the NFI family of transcription factors have both oncogenic and tumour-suppressive potential, depending on the context. This holds true across different tumour types, but also applies to the role of the different NFI family members within a single tumour type. For instance, NFIB
Acknowledgements
KSC was supported by a University of Queensland (UQ) International Postgraduate Student Scholarship and JWCL by an Australian Government Research Training Program Scholarship and UQ Centennial Scholarship. LJR was supported by an NHMRC Principal Research Fellowship (GNT1120615). JB was supported by the Scott Canner Young Researcher Grant from Tour de Cure. This work was supported by National Health and Medical Research Council project grant (GNT1100443 to LJR) and Ride for Rhonda.
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