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 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 N...
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2018-12-01
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| Series: | Cancers |
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| author | Lu Qiu Meng Wang Shaofan Hu Xufang Ru Yonggang Ren Zhengwen Zhang Siwang Yu Yiguo Zhang |
| author_facet | Lu Qiu Meng Wang Shaofan Hu Xufang Ru Yonggang Ren Zhengwen Zhang Siwang Yu Yiguo Zhang |
| author_sort | Lu Qiu |
| collection | DOAJ |
| description | 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 <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Further investigation of xenograft model mice showed that malignant growth of <i>Nrf1α<sup>−/</sup><sup>−</sup></i>-derived tumors is almost abolished by silencing of Nrf2, while <i>Nrf1α<sup>+/</sup><sup>+</sup></i>-tumor is markedly repressed by an inactive mutant (i.e., <i>Nrf2<sup>−/</sup><sup>−</sup><sup>ΔTA</sup></i>), but largely unaffected by <i>a priori</i> constitutive activator (i.e., <i>caNrf2<sup>ΔN</sup></i>). 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 <i>Nrf1</i> 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. |
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| spelling | doaj.art-7f5a31bde18b492f81866a39b264629c2023-09-03T01:34:07ZengMDPI AGCancers2072-66942018-12-01101252010.3390/cancers10120520cancers10120520Oncogenic 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 RepressorLu Qiu0Meng Wang1Shaofan Hu2Xufang Ru3Yonggang Ren4Zhengwen Zhang5Siwang Yu6Yiguo Zhang7The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaThe Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaThe Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaThe Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaThe Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaInstitute of Neuroscience and Psychology, School of Life Sciences, University of Glasgow, 42 Western Common Road, Glasgow G22 5PQ, Scotland, United KingdomState 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, ChinaThe Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, ChinaLiver-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 <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in <i>Nrf1α<sup>−/</sup><sup>−</sup></i> cells. Further investigation of xenograft model mice showed that malignant growth of <i>Nrf1α<sup>−/</sup><sup>−</sup></i>-derived tumors is almost abolished by silencing of Nrf2, while <i>Nrf1α<sup>+/</sup><sup>+</sup></i>-tumor is markedly repressed by an inactive mutant (i.e., <i>Nrf2<sup>−/</sup><sup>−</sup><sup>ΔTA</sup></i>), but largely unaffected by <i>a priori</i> constitutive activator (i.e., <i>caNrf2<sup>ΔN</sup></i>). 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 <i>Nrf1</i> 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.https://www.mdpi.com/2072-6694/10/12/520Nrf1αNrf2Keap1PTENCOX1COX2AP-1miR-22proteasometumor repressortumor promoterregulatory networksnon-alcoholic steatohepatitishepatomaoxidative stress |
| spellingShingle | Lu Qiu Meng Wang Shaofan Hu Xufang Ru Yonggang Ren Zhengwen Zhang Siwang Yu Yiguo Zhang 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 Nrf1α Nrf2 Keap1 PTEN COX1 COX2 AP-1 miR-22 proteasome tumor repressor tumor promoter regulatory networks non-alcoholic steatohepatitis hepatoma oxidative stress |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Nrf1α Nrf2 Keap1 PTEN COX1 COX2 AP-1 miR-22 proteasome tumor repressor tumor promoter regulatory networks non-alcoholic steatohepatitis hepatoma oxidative stress |
| url | https://www.mdpi.com/2072-6694/10/12/520 |
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