Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1α^−/− cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1α^−/− cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1α^−/−-derived tumors is almost abolished by silencing of Nrf2, while Nrf1α^+/+-tumor is markedly repressed by an inactive mutant (i.e., Nrf2^−/−ΔTA), but largely unaffected by a priori constitutive activator (i.e., caNrf2^ΔN). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity. Though as a tumor promoter, Nrf2 can also, in turn, directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. In view of such mutual inter-regulation by between Nrf1α and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1α, Nrf2 or both.

Objective: NFE2L3 is a member of the cap 'n' collar basic-region leucine zipper family. NFE2L3 has turned out to be associated with oxidative stress, but the relevance of NFE2L3 in hepatocellular carcinoma (HCC) has remained elusive. This study aimed to investigate the role of NFE2L3 in HCC and explore underlying mechanisms.

Nuclear factor erythroid 2‐like 3 (NFE2L3) is a member of the cap ‘n’ collar basic‐region leucine zipper (CNC‐bZIP) transcription factor family that plays a vital role in modulating oxidation–reduction steady‐state and proteolysis. Accumulating evidence suggests that NFE2L3 participates in cancer development; however, little is known about the mechanism by which NFE2L3 regulates hepatocellular carcinoma (HCC) cell growth. Here, we confirmed that NFE2L3 promotes HCC cell proliferation by acting as a transcription factor, which directly induces the expression of proteasome and interferon‐stimulated gene 15 (ISG15) to enhance the proteasome‐dependent degradation of ISGylated p53. Post‐translational ISGylation abated the stability of p53 and facilitated HCC cell growth. In summary, we uncovered the pivotal role of NFE2L3 in promoting HCC cell proliferation during proteostasis. This finding may provide a new target for the clinical treatment of HCC.

Background Although oxidative stress is strongly connected to the initiation and progression of cancer, the underlying molecular pathways remain unknown. The redox regulator CNC-bZIPs are important transcription factor groups that mediate the interplay of environmental cues and intercellular homeostasis. Immune checkpoint molecules (ICMs) are key molecules that mediate the communication between immune cells and tumor cells. This research sought to explore the transcriptional regulatory effects of CNC-bZIPs on ICMs. Methods The potential role of CNC-bZIPs in tumors and the correlation between CNC-bZIPs and ICMs were analyzed by the gene expression characteristics, survival analysis, and correlation analysis in TCGA data. And the transcriptional regulatory effects of CNC-bZIPs on ICMs were verified through cis acting element analysis and promoter activity reporter experiments. Results In this study, we found that high expression of CNC-bZIPs predicted poor prognosis, and we determined that CNC-bZIPs are universally connected to ICMs by analyzing gene expression correlation in TCGA tumor data. Specifically, CD47 and CD274 exhibit universally positive correlation with CNC-bZIPs in various tumor tissues. Promoter analysis revealed that there are several ARE elements, which are specifically recognized by CNC-bZIPs, in the promoter regions of CD47 and CD274 genes. Overexpression of NFE2L1 and NFE2L2 was used to explore the regulation of common ICM genes, such as CD47 and CD274, and the transcriptional regulatory effect of CNC-bZIPs on ICMs was confirmed using promoter activity reporter experiments. Conclusion In this study, the universal and systematic transcriptional regulatory role of the CNC-bZIP transcription factor family on ICMs was discovered. According to this study, the results and conclusions drawn are based on gene expression correlation and promoter activity assays, the CNC-bZIPs/ICMs transcriptional regulatory axis was revealed to be a potential regulatory axis that may drive redox signaling and anti-tumor immune responses.

Antitumor transcription activator NFE2L1, with the functions to regulate redox homeostasis, protein turnover, and material metabolism, plays an important role in embryonic development and specialization of tissue and organ functions. Deficiency of NFE2L1 gene in different regions yields distinct phenotypes, suggesting that NFE2L1 may have a transcription factor-independent function. Here we originally discovered the non-transcription factor activity of NFE2L1 by constructing a truncated protein-NFE2L1 ^ΔC without 152 aa at the C-terminus which lost the transcription factor activity. The regulation of NFE2L1 on redox homeostasis, proteasome function, and immune response mainly depends on its transcription activator function in nucleus, while the regulation on metabolism, ribosome function, and canceration is germanely to its non-transcription factor activity in cytoplasm. Surprisingly, the results indicated the tumor suppressive effect of NFE2L1 by repression of Wnt/β-catenin signaling in a non-transcription factor manner, indicating the potential value of NFE2L1 as a therapeutic target in clinical cancer treatment independent of its transcription factor activity. Our observations reveal the non-transcription factor activity of NFE2L1 for the first time, and lay foundation for the basic and applied research of NFE2L1.