Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor

Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of nonalcoholic 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 Nrf1 alpha-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1 alpha(-/-) cells. Loss of Nrf1 alpha leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1 alpha(-/-) cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1 alpha(-/-)-derived tumors is almost abolished by silencing of Nrf2, while Nrf1 alpha(+/+)-tumor is markedly repressed by an inactive mutant (i.e., Nrf2(-/-)(Delta TA)) , but largely unaffected by a priori constitutive activator (i.e., caNrf2(Delta N)). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1 alpha and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1 alpha 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 Nrf1 alpha. and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1 alpha, Nrf2 or both.