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

作者：Lu Qiu, Meng Wang, Shaofan Hu, Xufang Ru, Yonggang Ren, Zhengwen Zhang, Siwang Yu, Yiguo Zhang · 发表于：Cancers · 年份：2018 · DOI：10.3390/cancers10120520 · 被引用次数：56 · 研究领域：Genomics, phytochemicals, and oxidative stress、Liver Disease Diagnosis and Treatment、Glutathione Transferases and Polymorphisms

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., caNrf2ΔN). 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-r...