NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate

Abstract

NFIX, a member of the nuclear factor I (NFI) family of transcription factors, is known to be involved in muscle and central nervous system embryonic development. However, its expression in adults is limited. Similar to other developmental transcription factors, NFIX has been found to be altered in tumors, often promoting pro-tumorigenic functions, such as leading to proliferation, differentiation, and migration. However, some studies suggest that NFIX can also have a tumor suppressor role, indicating a complex and cancer-type dependent role of NFIX. This complexity may be linked to the multiple processes at play in regulating NFIX, which include transcriptional, post-transcriptional, and post-translational processes. Moreover, other features of NFIX, including its ability to interact with different NFI members to form homodimers or heterodimers, therefore allowing the transcription of different target genes, and its ability to sense oxidative stress, can also modulate its function. In this review, we examine different aspects of NFIX regulation, first in development and then in cancer, highlighting the important role of NFIX in oxidative stress and cell fate regulation in tumors. Moreover, we propose different mechanisms through which oxidative stress regulates NFIX transcription and function, underlining NFIX as a key factor for tumorigenesis.

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

“…This decrease was concomitant with an increase in NFIX nuclear protein levels ( Figure 3C ), and number of NFIX-positive nuclei ( Figure 3D ). NFIX is a transcription factor that is responsible for the transition between embryonic and fetal myogenesis 4,33 , and has been shown to be highly expressed in C2C12 cells 20 . These results suggest that increased levels of NFIX may cause a shift towards a faulty fetal myogenesis, compromising the skeletal muscle differentiation process.…”

“…Accordingly, MuSCs can display a proliferation defect in the absence of Lama2 , as suggested by our in vitro data ( Figure 1C, D ), and by our previous findings showing a reduction in the number of PAX7 + cells in dy W fetuses 19 . Importantly, the absence of Lama2 impairs cell differentiation and fusion in vitro , which is accompanied by a decrease in the myogenic regulatory factors Myog ( Figure 3A ) and MYF5 ( Figure 3B,C ), and an increase in the transcription factor NFIX ( Figure 3C,D ), which may reveal an unevenly entrance in the fetal myogeneisis 4,33 . Since NFIX expression should gradually increase during fetal development to assure a smooth transition from embryonic to fetal stages 49 , it is possible that this drastic alteration promotes cycles of regeneration and degeneration, exacerbating disease pathology, as previously reported in the context of α-sarcoglycan ( Sgca null)- and dystrophin ( mdx) -deficient dystrophic mice 50 .…”

“…Differentiation and fusion of these MuSCs lead to the formation of secondary myotubes, marking the beginning of the secondary (or fetal) myogenesis. The transition between primary and secondary myogenesis is promoted by the transcription factor nuclear factor one X (NFIX), which activates fetal-specific genes and blocks embryonic genes 3,4 . Myogenesis is therefore a tightly regulated process involving the contribution of distinct players including transcription factors, growth factor-induced signaling pathways, and extracellular matrix (ECM) [5][6][7] .…”

Circular RNA hsa_circ_0049657 as a Potential Biomarker in Non-Small Cell Lung Cancer

“…MiR-647 and miR-1914 both target NFIX and reduce its expression [14]. The role of NFIX in cancer proliferation, migration, and invasion has been linked to the expression of noncoding RNAs [15].…”