Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

SUMMARY Liver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1α-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1α −/− cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1α −/− cells. Further investigation of xenograft mice showed that malignant growth of Nrf1α −/− -derived tumor is almost abolished by silencing Nrf2, while Nrf1α +/+ -tumor is markedly repressed by inactive Nrf2 −/−ΔTA , but unaffected by a priori constitutive activator of caNrf2 ΔN . Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. HIGHLIGHTS Opposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2 Malignant growth of Nrf1α −/− -derived tumor is prevented by silencing Nrf2 Hyper-activation of Nrf2 by Nrf1α −/− results from decreased Keap1 and PTEN Nrf1α +/+ -tumor is repressed by Nrf2 −/−ΔTA , but unaltered by its active caNrf2 ΔN