Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression

Bhawe, Kaumudi; Roy, Deodutta

doi:10.1007/s13402-018-0395-3

Cited by 48 publications

(39 citation statements)

References 130 publications

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“…We for the first time show that NRF1 alone and/or, under carcinogenic estrogen-induced stress, contributes to generating highly invasive mesenchymal BCSCs via EMT. Our results also showed that heterogeneous BCSCs are produced by exposure to E2 and/or ectopic expression of molecular risk factor - differentiate into all cell types of the mammary gland 34,35 . Our results showed that the expression of NANOG, OCT4, and SOX2 were increased by NRF1.…”

Section: Discussionsupporting

confidence: 69%

“…Recent studies suggest that EMT contributes to the acquisition of cancer stem cell properties 12,20 . From ChIP-chip, ChIP-PET, and ChIP-seq analysis, we know not only which genes display altered expression when NRF1 activity is modulated but also which genomic loci are physically occupied by NRF1 4,5,11,34,35 .…”

Section: Discussionmentioning

confidence: 99%

“…The above studies provide strong support for our concept that NRF1 plays an important role in the development of breast cancer.The mechanism by which NRF1 may reprogram adult breast epithelial cells to acquire cancer stem cell properties is not clear. We have recently shown that NRF1 motifs were present in genes of signaling pathways of all ten HALL MARKS linked to malignant transformation and progression34,35 . In addition to controlling mitochondrialbiogenesis, by activating or repressing the cancer HALL MARK genes, NRF1 may play a critical role in the acquisition of human cancer hallmark features.…”

mentioning

confidence: 99%

“…The percentage of NRF1 promoter occupation seems to be dependent on cell type. Embryonic stem cells have been shown to have roughly 33% of all active genes bound by NRF1 within 1 kb of the transcriptional start site34,36 . The mechanism by which It appears that NRF1 transcriptional programming may contribute to the acquisition of BCSCs via epithelial to mesenchymal transition (EMT)39,40 .…”

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confidence: 99%

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NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

Das¹,

Felty²,

Poppiti³

et al. 2018

Preprint

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Transcription factor activity of the nuclear respiratory factor 1 protein (NRF1) is increased in breast cancer. Whether this gain of NRF1 activity is directly involved in breast cancer remains unknown. Herein, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cells (BCSCs) composed of more than ten distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the sub-populations of BCSCs arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of BCSCs through EMT. CXCR4 was activated by NRF1 in a redox dependent manner during malignant transformation. NRF1-induced BCSCs were able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1 driven breast tumorigenesis in the experimental model, higher levels of NRF1 protein expression were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSCs and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Additionally, the discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens the new avenues for mechanistic therapeutic strategy against breast cancer.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

Das¹,

Felty²,

Poppiti³

et al. 2018

Preprint

Self Cite

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“…The novel roles of NRF1 has been reported in cancer development and progression through its interplay with the transcription factors E2F4 and MYC [25]. Thus, NRF1 inevitably need to be taken into account when evaluating prognostics and therapeutic options for cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Respiratory Factor 1 Associated with Prognosis and Immune Infiltration in Hepatocellular Carcinoma

Wang

Huang

Zhang

et al. 2020

Preprint

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Background: Recent studies have shown that functional mitochondria are essential for cancer cells. Nuclear respiratory factor 1 (NRF1) is a transcription factor that activates mitochondrial biogenesis and the expression of the respiratory chain, but little is known about its prognostic value and tumor-infiltrating lymphocytes association. Here, we evaluated the association among expression of NRF1, clinicopathological characteristics, survival and immune infiltration in hepatocellular carcinoma (HCC).Methods: We used the Tumor Immune Estimation Resource (TIMER) to analyze the difference of NRF1 mRNA expression in human cancers. Clinical-pathological information and follow-up data were collected from HCC (n = 171) and chronic hepatitis (n = 113) patients. NRF1 expression were scored based on the percentage and intensity of immunohistochemical staining in pathological slides. Correlations between clinical features and the expression of NRF1 were evaluated by Chi-square test, Kaplan-Meier curves, logrank tests and multivariate Cox regression analysis. The correlations between NRF1 expression and gene marker sets of tumor infiltrating lymphocytes (TILs) were analyzed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Results: NRF1 mRNA expression was significantly higher in HCC than in normal tissue. Compared with chronic hepatitis, more frequency of NRF1 high expression are found in HCC (31.58 % vs 13.27 %, P < 0.001, P < 0.001). In addition, the NRF1 expression was significantly associated with hepatic cirrhosis (P = 0.021) and vascular invasion (P = 0.025). NRF1 expression was also a significant independent predictor of survival in HCC (P = 0.003; HRadj = 0.20; 95% CI = 0.09 – 0.44). NRF1 showed positively correlated with TILs, including B cell (r = 0.384, P = 1.68e-13), CD8+ T cells (r = 0.246, P = 3.99e-06), CD4+ T cells (r = 0.535, P = 6.90e-27), macrophage (r = 0.506, P = 1.52e-23), neutrophils (r = 0.465, P = 6.08e-20) and dendritic cell (r = 0.404, P = 8.61e-15). The marker genes of TILs correlated significantly with NRF1 expression.Conclusions: NRF1 expression was a useful independent prognostic factor and correlated with tumor immune infiltration in HCC.

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Loss of high‐temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia

et al. 2020

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Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possesses their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However, little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health‐related quality of life, disability, and premature death in older people. High‐temperature requirement protein A2 (HtrA2/Omi) is a mitochondrial protease and plays an important role in mitochondrial proteostasis. HtrA2mnd2(−/−) mice harboring protease‐deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in muscle degeneration. Using motor functional, histological, and molecular biological methods, we characterized the phenotype of HtrA2mnd2(−/−) muscle. Furthermore, we isolated the gastrocnemius muscle of HtrA2mnd2(−/−) mice and determined expression of genes in mitochondrial unfolded protein response (UPRmt), mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis. Here, we showed that HtrA2/Omi protease deficiency induced denervation‐independent skeletal muscle degeneration with sarcopenia phenotypes. Despite mitochondrial hypofunction, upregulation of UPRmt and mitohormesis‐related genes and elevated total reactive oxygen species (ROS) production were not observed in HtrA2mnd2(−/−) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nuclear DNA‐ and mitochondrial DNA‐encoded ETC subunits, which is in consistent with their transcription factors, nuclear respiratory factors 1 and 2, and coactivator peroxisome proliferator‐activated receptor γ coactivator 1α. These results reveal that loss of HtrA2/Omi protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.

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Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression

Cited by 48 publications

References 130 publications

NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

NRF1-Mediated Oncogenic Reprogramming Drives Estrogen-Induced Breast Carcinogenesis

Nuclear Respiratory Factor 1 Associated with Prognosis and Immune Infiltration in Hepatocellular Carcinoma

Loss of high‐temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia

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