A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

Zhu, Yanhua; Hu, Shaofan; Ru, Xufang; Zheng, Ze; Fan, Z.; Qiu, Lu; Zhang, Yiguo

doi:10.1101/655159

Cited by 8 publications

(1 citation statement)

References 61 publications

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“…Our recent work has unraveled that knockout of the human full-length Nrf1 (including TCF11 and its derivates, collectively called Nrf1 −/− ) by its Nfe2l1 gene-editing from hepatoma cells leads to aberrant accumulation of Nrf2 [24,36]. Despite such the activation of Nrf2 and its mediated antioxidant genes, they appear to do nothing to prevent, but conversely promote deterioration of Nrf1 −/− -derived tumor in the invasion and metastasis [24,37].…”

Section: Introductionmentioning

confidence: 99%

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Chen

Wang

et al. 2019

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Our previous work revealed that Nrf1 exerts a tumor-repressing effect because its genomic loss (to yield Nrf1 −/− ) results in oncogenic activation of Nrf2 and target genes. Interestingly, -catenin is concurrently activated by loss of Nrf1 in a way similar to -catenin-driven liver tumor. However, a presumable relationship between Nrf1 and -catenin is not as yet established. Here, we demonstrate that Nrf1 enhanced ubiquitination of -catenin for targeting to proteasomal degradation. Conversely, knockdown of Nrf1 by its short-hairpin RNA (shNrf1) caused accumulation of -catenin so as to translocate the nucleus, allowing activation of a subset of Wnt−-catenin signaling responsive genes, which leads to the epithelial-mesenchymal transition (EMT) and related cellular processes. Such silencing of Nrf1 resulted in malgrowth of human hepatocellular carcinoma, along with malignant invasion and metastasis to the lung and liver in xenograft model mice. Further transcriptomic sequencing unraveled significant differences in the expression of both Wnt/-catenin-dependent and -independent responsive genes implicated in the cell process, shape and behavior of the shNrf1-expressing tumor. Notably, we identified that -catenin is not a target gene of Nrf1, but this CNC-bZIP factor contributes to differential or opposing expression of other critical genes, such as CDH1, Wnt5A, Wnt11A, FZD10, LEF, TCF4, SMAD4, MMP9, PTEN, PI3K, JUN and p53, each of which depends on the positioning of distinct cis-regulatory sequences (e.g., ARE and/or AP-1 binding sites) in the gene promoter contexts. In addition, altered expression profiles of some Wnt−-catenin signaling proteins were context-dependent, as accompanied by decreased abundances of Nrf1 in the clinic human hepatomas with distinct differentiation. Together, these results corroborate the rationale that Nrf1 acts as a bona fide dominant tumor-repressor, by its intrinsic inhibition of Wnt−-catenin signaling and relevant independent networks in cancer development and malignant progression.repressors Bach1 (BTB and CNC homology 1) and Bach2 [6,7], together with the recently-identified Nach (Nrf and CNC homology) proteins existing in marine bacteria to early diverging metazoans [3,4]. These CNC/Nach-bZIP family members share a common evolutionary ancestor with the Maf (musculoaponeurotic fibrosarcoma oncogene) family, including sMaf (small Maf) proteins [4]. They play a host of vital, and even indispensable, roles in regulating distinct subsets of target genes involved in antioxidant, detoxification, redox metabolism, proteasomal degradation, adaptive cytoprotection, and other physio-pathological responses to diverse cellular stresses [6][7][8]. Such genes are regulated transcriptionally by a functional heterodimer of each CNC-bZIP factor (except Skn-1) with a cognate partner sMaf or another bZIP protein, which directly binds the antioxidant and electrophile response elements (AREs/EpREs) and/or other cis-regulatory homologues (e.g., AP-1 binding site) within the gene promoter reg...

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Section: Introductionmentioning

confidence: 99%

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Chen

Wang

et al. 2019

Preprint

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Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Zhang

Deng

Xiang

et al. 2020

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There is hitherto no literature available for explaining two distinct, but confused Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated -Pal). Thus, we have here identified that Nfe2l1 Nrf1 and -Pal NRF1 exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1 / leads to substantial decreases in expression levels of -Pal NRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2 / MEFs, with an exception that GSTa1 and Aldh1a1 were distinguishably up-regulated in Nfe2l1 / MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of -Pal NRF1 and TFAM were validated in Keap1 / MEFs. However, human -Pal NRF1 expression was unaltered by hNfe2l1 / , hNfe2l2 /TA or even hNfe2l1 / +siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occured in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2 and co-target genes were down-expressed in -Pal NRF1/ MEFs. On the contrary, up-regulation of human Nfe2l1, Nfe2l2 and relevant reporter genes took place after silencing of -Pal NRF1 , but their down-regulation occurred upon ectopic expression of -Pal NRF1 .Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides -Pal NRF1 . Overall, these across-talks amongst Nfe2l1, Nfe2l2 and -Pal NRF1 , along with Pitx2, are integrated from the endoplasmic reticulum to the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the cellular respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. Keywords: Nfe2l1/Nrf1, Nfe2l2/Nrf2, -Pal NRF1 , TFAM, Pitx2, cap'n'collar (CNC), antioxidant response element (ARE), nuclear-to-mitochondrial respiratory system, and ER-nuclear-mitochondrial (ENUM) communication Running title: Two distinct Nrf1 factors responsible for cellular antioxidant and respiration.

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Differential yet integral contributions of Nrf1 and Nrf2 in the human antioxidant cytoprotective response against tert-butylhydroquinone as a pro-oxidative stressor

Wufuer

Fan

Liu

et al. 2021

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In the past 25 years, Nrf2 had been preferentially parsed as a master hub of regulating antioxidant, detoxification and cytoprotective genes, albeit as a matter of fact that Nrf1, rather than Nrf2, is indispensable for cell homeostasis and organ integrity during normal growth and development. Here, distinct genotypic cell lines (Nrf1α−/−, Nrf2−/−ΔTA and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tBHQ as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also cannot 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 and hence resulted in obvious oxidative stress, but can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG to GSH. Conversely, a remarkable increase of Nrf1 expression was resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, no matter if it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E and MT2), as well on the ROS-scavenging activities of SOD and CAT, 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. Keywords: Nrf1; Nrf2; antioxidant; oxidative stress; reactive oxygen species; tert-butylhydroquinone (tBHQ).

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A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

Cited by 8 publications

References 61 publications

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Differential yet integral contributions of Nrf1 and Nrf2 in the human antioxidant cytoprotective response against tert-butylhydroquinone as a pro-oxidative stressor

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