Resumen
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 Nrf1a-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1a-/- cells. Loss of Nrf1a leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1a-/- cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1a-/--derived tumors is almost abolished by silencing of Nrf2, while Nrf1a+/+-tumor is markedly repressed by an inactive mutant (i.e., Nrf2-/-?TA), but largely unaffected by a priori constitutive activator (i.e., caNrf2?N). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1a and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1a 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 Nrf1a and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1a, Nrf2 or both.