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Nuclear Respiratory Factor 1 (NRF1) Transcriptional Activity-Driven Gene Signature Association with Severity of Astrocytoma and Poor Prognosis of Glioblastoma

Molecular Neurobiology volume 57, pages 3827–3845 (2020)Cite this article

Abstract

Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM. NRF1 has higher mRNA expression and transcription factor activity in astrocytoma compared to non-tumor brain tissue. NRF1 activity also correlated with the aggressiveness of cancer. Increased NRF1 TF activity coupled with overexpression of RHOG was associated with poor survival of GBM patients. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition and cell cycle progression. Overexpression of CDK4, AKT1, APAF1, HDAC1, NBN, TGFB1, & TNFRSF1A and downregulation of CASP3, IL7, STXBP1 and OPA1 predicted GBM malignancy in high expressors of NRF1 activity. Increased expression of the NRF1 motif containing genes, H6PD, NAT10, NBEAL2, and RNF19B predicted poor survival of IDH1 wild-type GBM patients. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets - LDHA, ZMAT3, NSUN2, ARMC5, NDEL1, CLPTM1L, ALKBH5, YIPF5, PPP2CA, and TFG. These findings suggest that aberrant NRF1 activity may contribute to the pathogenesis of GBM and severity of astrocytoma. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.

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References

  1. Tamimi AF, Juweid M (2017) Epidemiology and Outcome of Glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications. Chapter 8. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470003 https://doi.org/10.15586/codon.glioblastoma.2017.ch8.

  2. Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister SM, Nishikawa R, Rosenthal M et al (2015) Glioma. Nature Reviews Disease Primers 1:15017. https://doi.org/10.1038/nrdp.2015.17

    Article  PubMed  Google Scholar 

  3. Koshy M, Villano JL, Dolecek TA, Howard A, Mahmood U, Chmura SJ, Weichselbaum RR, McCarthy BJ (2012) Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neuro-Oncol 107:207–212. https://doi.org/10.1007/s11060-011-0738-7

    Article  Google Scholar 

  4. Stupp R, Mason WP, van den Bent M, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA et al (2005) Radiotherapy plus concomitant and adjuvant Temozolomide for Glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Pennacchio LA, Loots GG, Nobrega MA, Ovcharenko I (2007) Predicting tissue-specific enhancers in the human genome. Genome Res 17:201–211. https://doi.org/10.1101/gr.5972507

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Li Z, Cogswell M, Hixson K, Brooks-Kayal AR, Russek SJ (2018) Nuclear respiratory factor 1 (NRF-1) controls the activity dependent transcription of the GABA-A receptor Beta 1 subunit gene in neurons. Front Mol Neurosci 11:285. https://doi.org/10.3389/fnmol.2018.00285

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Das JK, Felty Q, Poppiti R, Jackson RM, Roy D (2018) Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis. Cells 7(12):234.https://doi.org/10.3390/cells7120234

  8. Bhawe K, Roy D (2018) Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression. Cell Oncol 41:465–484. https://doi.org/10.1007/s13402-018-0395-3

    CAS  Article  Google Scholar 

  9. Sartor MA, Leikauf GD, Medvedovic M (2009) LRpath: A logistic regression approach for identifying enriched biological groups in gene expression data. Bioinformatics 25:211–217. https://doi.org/10.1093/bioinformatics/btn592

    CAS  Article  PubMed  Google Scholar 

  10. Falco MM, Bleda M, Carbonell-Caballero J, Dopazo J (2016) The pan-cancer pathological regulatory landscape. Sci Rep 6:39709. https://doi.org/10.1038/srep39709

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang J, Jiao J (2015) Molecular biomarkers for embryonic and adult neural stem cell and neurogenesis. Biomed Res Int 2015:727542–727514. https://doi.org/10.1155/2015/727542

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Kunkle BW, Yoo C, Roy D (2013) Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma. PLoS One 8:e64140. https://doi.org/10.1371/journal.pone.0064140

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Mondal G, Stevers M, Goode B, Ashworth A, Solomon DA (2019) A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers. Nat Commun 10:1686. https://doi.org/10.1038/s41467-019-09659-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y et al (2018) The p53 Pathway in Glioblastoma. Cancers 10:297. https://doi.org/10.3390/cancers10090297

  15. Zuccarini M et al (2018) The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor. Genes (Basel) 9(2):105. https://doi.org/10.3390/genes9020105

  16. Zhao M, Kong L, Liu Y, Qu H (2015) dbEMT: an epithelial-mesenchymal transition associated gene resource. Sci Rep 5:11459. https://doi.org/10.1038/srep11459

  17. Merry TL, Ristow M (2016) Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol 594:5195–5207. https://doi.org/10.1113/JP271957

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Cam H, Balciunaite E, Blais A, Spektor A, Scarpulla RC, Young R, Kluger Y, Dynlacht BD (2004) A common set of gene regulatory networks links metabolism and growth inhibition. Mol Cell 16:399–411. https://doi.org/10.1016/j.molcel.2004.09.037

    CAS  Article  PubMed  Google Scholar 

  19. Demir O, Aysit N, onder Z, Turkel N, Ozturk G, Sharrocks AD, Kurnaz IA (2011) ETS-domain transcription factor Elk-1 mediates neuronal survival: SMN as a potential target. Biochim Biophys Acta 1812:652–662. https://doi.org/10.1016/j.bbadis.2011.02.012

    CAS  Article  PubMed  Google Scholar 

  20. Pantarelli C, Welch HCE (2018) Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. Eur J Clin Investig 48(Suppl. 2):e12939. https://doi.org/10.1111/eci.12939

    CAS  Article  Google Scholar 

  21. Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, Rushing E, Eschbacher J et al (2012) The small GTPase RhoG mediates glioblastoma cell invasion. Mol Cancer 11:65. https://doi.org/10.1186/1476-4598-11-65

  22. Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, Purushotham A, Li X (2010) Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol 30(19):4712–4721. https://doi.org/10.1128/MCB.00657-10

  23. Liu TF, McCall CE (2013) Deacetylation by SIRT1 reprograms inflammation and cancer. Genes Cancer 4(3–4):135–147. https://doi.org/10.1177/1947601913476948

  24. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Wu H, Chen S, Yu J, Li Y, Zhang XY, Yang L, Zhang H, hou Q et al (2018) Single-cell Transcriptome analyses reveal molecular signals to intrinsic and acquired paclitaxel resistance in esophageal squamous Cancer cells. Cancer Lett 420:156–167. https://doi.org/10.1016/j.canlet.2018.01.059

    CAS  Article  PubMed  Google Scholar 

  26. Yamamoto K, Okamoto A, Isonishi S, Ochiai K, Ohtake Y (2001) A Novel Gene, CRR9, Which Was Up-Regulated in CDDP-Resistant Ovarian Tumor Cell Line, Was Associated with Apoptosis. Biochemical and Biophysical Research Communications. Biochem Arch 280(4):1148–1154. https://doi.org/10.1006/bbrc.2001.4250

  27. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K et al (2000) Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium Nat Genet 25:25–29. https://doi.org/10.1038/75556

  28. The Gene Ontology Consortium (2019)The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res 47:D330–D338. https://doi.org/10.1093/nar/gky1055

  29. Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD (2019) PANTHER version 14: More genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res 47:D419–D426. https://doi.org/10.1093/nar/gky1038

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

We are grateful to the United States-India Educational Foundation for a Senior US Fulbright Nehru Scholar Award to DR.

Availability of Data and Materials

We used public datasets in this study and details of analysis used in the current study are available from the first author or corresponding author upon request.

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Affiliations

  1. Department of Environmental Health Sciences, Florida International University, Miami, FL, 33199, USA

    Kaumudi Bhawe, Quentin Felty & Deodutta Roy

  2. Department of Biostatistics, Florida International University, Miami, FL, 33199, USA

    Changwon Yoo

  3. National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India

    Nasreen Z. Ehtesham

  4. JH Institute of Molecular Medicine, Jamia Hamdard, New Delhi, India

    Seyed E. Hasnain

  5. Institute of Neuroscience, Medanta-The Medicity, Gurugram, India

    Varindera Paul Singh & Ishani Mohapatra

Authors
  1. Kaumudi Bhawe
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  2. Quentin Felty
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  3. Changwon Yoo
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  4. Nasreen Z. Ehtesham
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  5. Seyed E. Hasnain
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  6. Varindera Paul Singh
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  7. Ishani Mohapatra
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  8. Deodutta Roy
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Contributions

The study was designed, analyzed and interpreted by DR and KB. KB was helped by QF and DR in writing the manuscript. SEH, NE, VS, IM and CW contributed in the preparation of the final version of the manuscript.

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Correspondence to Deodutta Roy.

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Bhawe, K., Felty, Q., Yoo, C. et al. Nuclear Respiratory Factor 1 (NRF1) Transcriptional Activity-Driven Gene Signature Association with Severity of Astrocytoma and Poor Prognosis of Glioblastoma. Mol Neurobiol 57, 3827–3845 (2020). https://doi.org/10.1007/s12035-020-01979-2

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  • DOI: https://doi.org/10.1007/s12035-020-01979-2

Keywords

  • NRF1 activity
  • CDK4
  • RHOG
  • Cancer stem cells
  • EMT
  • Glioblastoma