| Summary: | 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 <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Further investigation of xenograft model mice showed that malignant growth of <i>Nrf1α<sup>−/</sup><sup>−</sup></i>-derived tumors is almost abolished by silencing of Nrf2, while <i>Nrf1α<sup>+/</sup><sup>+</sup></i>-tumor is markedly repressed by an inactive mutant (i.e., <i>Nrf2<sup>−/</sup><sup>−</sup><sup>ΔTA</sup></i>), but largely unaffected by <i>a priori</i> constitutive activator (i.e., <i>caNrf2<sup>ΔN</sup></i>). 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 <i>Nrf1</i> 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.
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