Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression

Nuclear respiratory factor 1 (NRF1), historically perceived as a protein regulating genes controlling mitochondrial biogenesis, is now widely recognized as a multifunctional protein and as a key player in the transcriptional modulation of genes implicated in various cellular functions. Here, we present emerging data supporting novel roles of NRF1 in cancer development and progression through its interplay with the transcription factors E2F4 and MYC. To identify common human NRF1, E2F4 and MYC target genes, we analyzed the Encyclopedia of DNA Elements (ENCODE) NRF1 ChIP-Seq data. By doing so, we identified 9253 common target genes with NRF1, E2F4 and MYC binding motifs. NRF1 binding motifs were found to be present in genes operating in signaling pathways governing all hallmarks of malignant transformation and progression, including proliferation, invasion, self-renewal and apoptosis.In addition to controlling mitochondrial biogenesis NRF1, in conjunction with E2F4 and MYC, may play a critical role in the acquisition of human cancer characteristics. Additionally, NRF1 may orchestrate both MYC and E2F4 to regulate common target genes linked to multiple networks in the development and progression of cancer. A comprehensive understanding of this dynamic interplay will set the stage, not only for the design of novel treatment strategies, but also for the discovery of pan-cellular transcription factor regulatory strategies to predict cancer risk, therapy response and patient prognosis.