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

Qiu, Lu; Wang, Meng; Hu, Shaofan; Ru, Xufang; Ren, Yong; Yu, Siwang; Zhang, Yiguo

doi:10.1101/403220

Cited by 5 publications

(5 citation statements)

References 104 publications

(114 reference statements)

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“…The western blotting result showed that NFE2L1 knockdown could efficiently elevate the expression of NFE2L2, HMOX1, and PTGS2 and decrease kelch like ECH associated protein 1 (KEAP1) (Fig. 4F), which were consistent with our previous results (Qiu et al, 2018). Then the changes in the protein levels of the key enzymes of sugar metabolism were detected.…”

Section: Nfe2l1 Deficiency Results In the Reprogramming Of Glucose Metabolism And Exacerbates The Warburg Effectsupporting

confidence: 90%

“…In NFE2L1 knockdown cells, the ROS level was increased more than 6 times in comparison with the control group after glucose deprivation for 6 hours, indicating the high levels of oxidative damage of NFE2L1 knockdown cells. These results were in accordance with previous studies that glucose starvation resulted in strong oxidative stress to induce cell death after NFE2L1 knockout (Qiu et al, 2018;Zhu et al, 2020).…”

Section: Nfe2l1 Deficiency Disrupts Cellular Energy Metabolism Signals and Induces Cell Death By Glucose Starvationsupporting

confidence: 94%

“…As the results shown in Fig. 4B, increase of heme oxygenase 1 (HMOX1) and prostaglandin-endoperoxide synthase 2 (PTGS2/COX2), and decrease of PTGS1 were detected accompanied by NFE2L1 knockdown, suggesting the loss of function of NFE2L1 (Qiu et al, 2018). HK1, the key enzyme involved in catalyzing the conversion of glucose to glucose-6-phosphate, was significantly increased.…”

Section: Nfe2l1 Deficiency Results In the Reprogramming Of Glucose Metabolism And Exacerbates The Warburg Effectmentioning

confidence: 71%

“…However, the underlying molecular mechanism by which NFE2L1 affects glucose metabolism remains to be explored. As a transcription factor, NFE2L1 could influence thousands of downstream genes with various functions (Cui et al, 2020;Liu et al, 2019;Qiu et al, 2018), making it difficult to identify the detailed mechanism of NFE2L1 in affecting glucose metabolism. Actually, the effect of NFE2L1 deficiency on glucose metabolic reprogramming is likely to be a systemic response.…”

Section: Nfe2l1 Knockdown Causes the Damage Of Mitochondrial Functionmentioning

confidence: 99%

“…Conventional knockout of NFE2L1 could induce strong oxidative stress injury and result in fetal death. Also, conditional knockout of NFE2L1 can increase cellular reactive oxygen species (ROS) level (Chen et al, 2003;Qiu et al, 2018;Xu et al, 2005;Zhang and Xiang, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

Yang

Zhao

et al. 2021

Preprint

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NFE2L1/Nrf1, the core regulator involved in redox homeostasis, is essential for embryonic development and material metabolism homeostasis. Dysfunction of NFE2L1 could induce multiple systemic metabolic diseases. However, the underlying molecular mechanism of NFE2L1 in regulating glycose and lipid metabolism is still unclear. Herein, the glucose starvation experiments verified that the loss of NFE2L1 in human hepatocarcinoma HepG2 cells would lead to a lethal phenotype when glucose deprivation. And the glucose uptake experiments showed that NFE2L1 could affect the absorption of glucose by cells. Then, selective inhibition of glucose metabolism and protein deglycosylation experiments showed that the glycation of NFE2L1 was regulated by glycolysis. These results suggested that NFE2L1 functioned as both the sensor and the regulator of glucose homeostasis. Transcriptome, metabolome and seahorse results revealed that damage of NFE2L1 reprogrammed glucose metabolism and aggravated the Warburg effect. And the electron microscopy results revealed that NFE2L1 knockdown damaged the mitochondrial. Proteins Co-immunoprecipitation experiments demonstrated that NFE2L1 could sense the energy state and directly regulate AMPK signal. The novel AMP/NFE2L1/AMPK signaling pathway that discovered in this study is not only a further improvement of AMPK signal, but also a key node that mediates the crosstalk between redox homeostasis and metabolism homeostasis.

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Section: Nfe2l1 Deficiency Results In the Reprogramming Of Glucose Metabolism And Exacerbates The Warburg Effectsupporting

confidence: 90%

Section: Nfe2l1 Deficiency Disrupts Cellular Energy Metabolism Signals and Induces Cell Death By Glucose Starvationsupporting

confidence: 94%

Section: Nfe2l1 Deficiency Results In the Reprogramming Of Glucose Metabolism And Exacerbates The Warburg Effectmentioning

confidence: 71%

Section: Nfe2l1 Knockdown Causes the Damage Of Mitochondrial Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

Yang

Zhao

et al. 2021

Preprint

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Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

et al. 2021

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In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)—rather than Nrf2—is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α−/−, Nrf2−/−ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α’s function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2’s functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.

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Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer

Zhang,

Liu,

Zhang

et al. 2024

Antioxidants

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Cancer cells subvert multiple properties of normal cells, including escaping strict cell cycle regulation, gaining resistance to cell death, and remodeling the tumor microenvironment. The hallmarks of cancer have recently been updated and summarized. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also named NRF1) belongs to the cap’n’collar (CNC) basic-region leucine zipper (bZIP) family. It acts as a transcription factor and is indispensable for maintaining both cellular homoeostasis and organ integrity during development and growth, as well as adaptive responses to pathophysiological stressors. In addition, NFE2L1 mediates the proteasome bounce-back effect in the clinical proteasome inhibitor therapy of neuroblastoma, multiple myeloma, and triple-negative breast cancer, which quickly induces proteasome inhibitor resistance. Recent studies have shown that NFE2L1 mediates cell proliferation and metabolic reprogramming in various cancer cell lines. We combined the framework provided by “hallmarks of cancer” with recent research on NFE2L1 to summarize the role and mechanism of NFE2L1 in cancer. These ongoing efforts aim to contribute to the development of potential novel cancer therapies that target the NFE2L1 pathway and its activity.

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

Cited by 5 publications

References 104 publications

Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer

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