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Open AccessArticle

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

1
The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, China
2
Institute of Neuroscience and Psychology, School of Life Sciences, University of Glasgow, 42 Western Common Road, Glasgow G22 5PQ, Scotland, United Kingdom
3
State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, No. 38 Xueyuan Rd., Haidian District, Beijing 100191, China
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(12), 520; https://doi.org/10.3390/cancers10120520
Received: 8 November 2018 / Revised: 5 December 2018 / Accepted: 10 December 2018 / Published: 17 December 2018
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-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. View Full-Text
Keywords: Nrf1α; Nrf2; Keap1; PTEN; COX1; COX2; AP-1; miR-22; proteasome; tumor repressor; tumor promoter; regulatory networks; non-alcoholic steatohepatitis; hepatoma; oxidative stress Nrf1α; Nrf2; Keap1; PTEN; COX1; COX2; AP-1; miR-22; proteasome; tumor repressor; tumor promoter; regulatory networks; non-alcoholic steatohepatitis; hepatoma; oxidative stress
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MDPI and ACS Style

Qiu, L.; Wang, M.; Hu, S.; Ru, X.; Ren, Y.; Zhang, Z.; Yu, S.; Zhang, Y. 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. Cancers 2018, 10, 520. https://doi.org/10.3390/cancers10120520

AMA Style

Qiu L, Wang M, Hu S, Ru X, Ren Y, Zhang Z, Yu S, Zhang Y. 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. Cancers. 2018; 10(12):520. https://doi.org/10.3390/cancers10120520

Chicago/Turabian Style

Qiu, Lu; Wang, Meng; Hu, Shaofan; Ru, Xufang; Ren, Yonggang; Zhang, Zhengwen; Yu, Siwang; Zhang, Yiguo. 2018. "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" Cancers 10, no. 12: 520. https://doi.org/10.3390/cancers10120520

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