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.
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 α-Pal). Thus, we have here identified that Nfe2l1Nrf1 and α-PalNRF1 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 α-PalNRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2-/- MEFs but with an exception that both GSTa1 and Aldh1a1 were distinguishably upregulated in Nfe2l1-/- MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of α-PalNRF1 and TFAM were validated in Keap1-/- MEFs. However, human α-PalNRF1 expression was unaltered by hNfe2l1α-/-, hNfe2l2-/-ΔTA, or even hNfe2l1α-/-+siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occurred in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2, and cotarget genes were downexpressed in α-PalNRF1+/- MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of α-PalNRF1, but their downregulation occurred upon ectopic expression of α-PalNRF1. Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides α-PalNRF1. Overall, these across-talks amongst Nfe2l1, Nfe2l2, and α-PalNRF1, along with Pitx2, are integrated from the endoplasmic reticulum towards the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the robust balance of distinct cellular oxidative respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. In addition, it is of crucial importance to note that, in view of such mutual interregulation of these transcription factors, it should be severely taken much cautions to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2, α-Pal or Pitx2, or their gain-of-functional mutants.
For insights into the fact that liver-specific knockout of Nrf1 leads to development of non-alcoholic steatohepatitis and spontaneous hepatoma, we previously found that loss of Nrf1α(i.e., a full-length isoform encoded by Nfe2l1) promotes HepG2-derived tumor growth in xenograft mice, but malgrowth of the xenograft tumor is significantly suppressed by knockout of Nrf2 (encoded by Nfe2l2). The mechanism underlying such marked distinctions in their pathologic phenotypes remains elusive, however, to date. Herein, we mined the transcriptome data of liver cancer from the TCGA database to establish a prognostic model of liver cancer and then calculated the predicted risk score of each cell line. The results indicated that knockout of Nrf1α significantly increased the risk score in HepG2 cells, whereas the risk score was reduced by knockout of Nrf2. Of note, stanniocalcin 2 (STC2, a biomarker of liver cancer, that is up-expressed in hepatocellular carcinoma (HCC) tissues with a reduction in the overall survival ratio of those patients) was augmented in Nrf1α-deficient cells, but diminished in Nrf2-deficient cells. Thereby, it is inferable that STC2 is likely involved in mediating the distinction between Nrf1α deficient and Nrf2 deficient.Such potential function of STC2 was further corroborated by a series of experiments combined with transcriptomic sequencing. The results unraveled that STC2 manifests as a dominant tumor-promoter, because the STC2-leading increases in clonogenicity of hepatoma cells and malgrowth of relevant xenograft tumor were almost completely abolished in STC2-deficient cells. Together, these demonstrate that STC2 could be paved as a novel potent therapeutic target, albeit as a diagnostic marker, for hepatocellular carcinoma.
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