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PARK7 maintains the stemness of glioblastoma stem cells by stabilizing epidermal growth factor receptor variant III

A Correction to this article was published on 08 February 2021

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Abstract

PARK7 is involved in many key cellular processes, including cell proliferation, transcriptional regulation, cellular differentiation, oxidative stress protection, and mitochondrial function maintenance. Deregulation of PARK7 has been implicated in the pathogenesis of various human diseases, including cancer. Here, we aimed to clarify the effect of PARK7 on stemness and radioresistance of glioblastoma stem cells (GSCs). Serum differentiation and magnetic cell sorting of GSCs revealed that PARK7 was preferentially expressed in GSCs rather than differentiated GSCs. Immunohistochemical staining showed enhanced expression of PARK7 in glioma tissues compared to that in normal brain tissues. shRNA-mediated knockdown of PARK7 inhibited the self-renewal activity of GSCs in vitro, as evidenced by the results of neurosphere formation, limiting dilution, and soft-agar clonogenic assays. In addition, PARK7 knockdown suppressed GSC invasion and enhanced GSC sensitivity to ionizing radiation (IR). PARK7 knockdown suppressed expression of GSC signatures including nestin, epidermal growth factor receptor variant III (EGFRvIII), SOX2, NOTCH1, and OCT4. Contrarily, overexpression of PARK7 in CD133- non-GSCs increased self-renewal activities, migration, and IR resistance, and rescued the reduction of GSC factors under shPARK7-transfected and serum-differentiation conditions. Intriguingly, PARK7 acted as a co-chaperone of HSP90 by binding to it, protecting EGFRvIII from proteasomal degradation. Knockdown of PARK7 increased the production of reactive oxygen species, inducing partial apoptosis and enhancing IR sensitivity in GSCs. Finally, PARK7 knockdown increased mouse survival and IR sensitivity in vivo. Based on these data, we propose that PARK7 plays a pivotal role in the maintenance of stemness and therapeutic resistance in GSCs.

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Fig. 1: Expression pattern of PARK7 in GSCs and non-GSCs, and GBM tissues.
Fig. 2: Effect of PARK7 KD on the GSC activity.
Fig. 3: Effect of PARK7 overexpression on GSC activity in CD133 non-GSCs.
Fig. 4: Rescue of serum differentiation-induced suppression of EGFRvIII and SOX2 expression by PARK7.
Fig. 5: Interaction of PARK7 with HSP90.
Fig. 6: Effect of PARK7 KD on cell death, ROS generation, and mouse survival.
Fig. 7: Effect of PARK7 KD on the combination therapy of mice with IR.

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References

  1. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics biology, and paths to treatment. Genes Dev. 2007;21:2683–710.

    CAS  PubMed  Google Scholar 

  2. Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE. Prognostic significance of operative MRI scans in glioblastoma multiforme. J Neurooncol. 1996;27:65–73.

    CAS  PubMed  Google Scholar 

  3. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CLL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29:1203–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    CAS  PubMed  Google Scholar 

  5. Osuka S, van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Investig. 2017;127:415–26.

    PubMed  Google Scholar 

  6. Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, et al. PARK7, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun. 1997;231:509–13.

    CAS  PubMed  Google Scholar 

  7. Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A. PARK7 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. 2004;2:e362.

    PubMed  PubMed Central  Google Scholar 

  8. Girotto S, Cendron L, Bisaglia M, Tessari I, Mammi S, Zanotti G, et al. PARK7 is a copper chaperone acting on SOD1 activation. J Biol Chem. 2014;289:10887–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee DH, Kim D, Kim ST, Jeong S, Kim JL, Shim SM, et al. PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5. Autophagy. 2018;14:1870–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. PARK7, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA. 2006;103:15091–6.

    CAS  PubMed  Google Scholar 

  11. Tillman JE, Yuan J, Gu G, Fazli L, Ghosh R, Flynt AS, et al. PARK7 binds androgen receptor directly and mediates its activity in hormonally treated prostate cancer cells. Cancer Res. 2007;67:4630–7.

    CAS  PubMed  Google Scholar 

  12. Vasseur S, Afzal S, Tardivel-Lacombe J, Park DS, Iovanna JL, Mak TW. PARK7/PARK 7 is an important mediator of hypoxia-induced cellular responses. Proc Natl Acad Sci USA. 2009;106:1111–6.

    CAS  PubMed  Google Scholar 

  13. Takahashi-Niki K, Niki T, Iguchi-Ariga SMM, Ariga H. Transcriptional regulation of PARK7. Adv Exp Med Biol. 2017;1037:89–95.

    CAS  PubMed  Google Scholar 

  14. Im JY, Lee KW, Woo JM, Junn E, Mouradian MM. PARK7 induces thioredoxin 1 expression through the Nrf2 pathway. Hum Mol Genet. 2012;21:3013–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Raninga PV, Di Trapani G, Tonissen KF. The multifaceted roles of PARK7 as an antioxidant. Adv Exp Med Biol. 2017;1037:67–87.

    CAS  PubMed  Google Scholar 

  16. Wang B, Abraham N, Gao G, Yang Q. Dysregulation of autophagy and mitochondrial function in Parkinson’s disease. Transl Neurodegener. 2016;5:19.

    PubMed  PubMed Central  Google Scholar 

  17. Gao X, Ning Y. Cancer and Parkinson’s disease: the odd couple. Drugs Today. 2011;47:215–22.

    CAS  Google Scholar 

  18. Macedo MG, Anar B, Bronner IF, Cannella M, Squitieri F, Bonifati V, et al. The PARK7L166P mutant protein associated with early onset Parkinson’s disease is unstable and forms higher-order protein complexes. Hum Mol Genet. 2003;12:2807–16.

    CAS  PubMed  Google Scholar 

  19. Olzmann JA, Brown K, Wilkinson KD, Rees HD, Huai Q, Ke H, et al. Familial Parkinson’s disease-associated L166P mutation disrupts PARK7 protein folding and function. J Biol Chem. 2004;279:8506–15.

    CAS  PubMed  Google Scholar 

  20. Cao J, Lou S, Ying M, Yang B. PARK7 as a human oncogene and potential therapeutic target. Biochem Pharm. 2015;93:241–50.

    CAS  PubMed  Google Scholar 

  21. Kawate T, Tsuchiya B, Iwaya K. Expression of PARK7 in cancer cells: its correlation with clinical significance. Adv Exp Med Biol. 2017;1037:45–59.

    CAS  PubMed  Google Scholar 

  22. Le Naour F, Misek DE, Krause MC, Deneux L, Giordano TJ, Scholl S, et al. Proteomics-based identification of RS/PARK7 as a novel circulating tumor antigen in breast cancer. Clin Cancer Res. 2001;7:3328–35.

    PubMed  Google Scholar 

  23. Han B, Wang J, Gao J, Feng S, Zhu Y, Li X, et al. PARK7 as a potential biomarker for the early diagnosis in lung cancer patients. Tumour Biol. 2017;39:1010428317714625.

    PubMed  Google Scholar 

  24. Kim Y, Ignatchenko V, Yao CQ, Kalatskaya I, Nyalwidhe JO, Lance RS, et al. Identification of differentially expressed proteins in direct expressed prostatic secretions of men with organ-confined versus extracapsular prostate cancer. Mol Cell Proteom. 2012;11:1870–84.

    Google Scholar 

  25. Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, et al. PARK7, a novel regulator of the tumor suppressor PTEN. Cancer Cell. 2005;7:263–73.

    CAS  PubMed  Google Scholar 

  26. Takahashi-Niki K, Kato-Ose I, Murata H, Maita H, Iguchi-Ariga SM, Ariga H. Epidermal growth factor-dependent Activation of the extracellular signal-regulated kinase pathway by PARK7 protein through its direct binding to c-Raf protein. J Biol Chem. 2015;290:17838–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Oh SE, Mouradian MM. Regulation of signal transduction by PARK7. Adv Exp Med Biol. 2017;1037:97–131.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Raninga PV, Trapani GD, Tonissen KF. Cross talk between two antioxidant systems, thioredoxin and PARK7: consequences for cancer. Oncoscience. 2014;1:95–110.

    PubMed  PubMed Central  Google Scholar 

  29. Parsanejad M, Zhang Y, Qu D, Irrcher I, Rousseaux MW, Aleyasin H, et al. Regulation of the VHL/HIF-1 pathway by PARK7. J Neurosci. 2014;34:8043–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin J, Park G, Kim TH, Hong JH, Kim YJ, Jin X, et al. Pigment epithelium-derived factor (PEDF) expression induced by EGFRvIII promotes self-renewal and tumor progression of glioma stem cells. PLOS Biol. 2015;13:e1002152.

    PubMed  PubMed Central  Google Scholar 

  31. Bowman RL, Wang Q, Carro A, Verhaak RG, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19:139–41.

    CAS  PubMed  Google Scholar 

  32. Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han SY, et al. Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res. 2014;74:1238–49.

    CAS  PubMed  Google Scholar 

  33. Rybak AP, Tang D. SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells. Cell Signal. 2013;25:2734–42.

    CAS  PubMed  Google Scholar 

  34. Knobbe CB, Revett TJ, Bai Y, Chow V, Jeon AH, Böhm C, et al. Choice of biological source material supersedes oxidative stress in its influence on PARK7 in vivo interactions with Hsp90. J Proteome Res. 2011;10:4388–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ahsan A, Ramanand SG, Whitehead C, Hiniker SM, Rehemtulla A, Pratt WB, et al. Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors. Neoplasia. 2012;14:670–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lavictoire SJ, Parolin DA, Klimowicz AC, Kelly JF, Lorimer IA. Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII. J Biol Chem. 2003;278:5292–9.

    CAS  PubMed  Google Scholar 

  37. Kim J, Lee JS, Jung J, Lim I, Lee JY, Park MJ. Emodin suppresses maintenance of stemness by augmenting proteosomal degradation of epidermal growth factor receptor/epidermal growth factor receptor variant III in glioma stem cells. Stem Cells Dev. 2015;24:284–95.

    CAS  PubMed  Google Scholar 

  38. Echeverría PC, Bernthaler A, Dupuis P, Mayer B, Picard D. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS ONE. 2011;6:e26044.

    PubMed  PubMed Central  Google Scholar 

  39. Bradley E, Bieberich E, Mivechi NF, Tangpisuthipongsa D, Wang G. Regulation of embryonic stem cell pluripotency by heat shock protein 90. Stem Cells. 2012;30:1624–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kudryavtsev VA, Khokhlova AV, Mosina VA, Selivanova EI, Kabakov A. Induction of Hsp70 in tumor cells treated with inhibitors of the Hsp90 activity: a predictive marker and promising target for radiosensitization. PLoS One. 2017;12:e0173640.

    PubMed  PubMed Central  Google Scholar 

  41. Zhong H, Yin H. Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria. Redox Biol. 2015;4:193–9.

    CAS  PubMed  Google Scholar 

  42. Zou Z, Chang H, Li H, Wang S. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis. 2017;22:1321–35.

    CAS  PubMed  Google Scholar 

  43. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.

    CAS  PubMed  Google Scholar 

  44. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.

    CAS  PubMed  Google Scholar 

  45. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.

    CAS  PubMed  Google Scholar 

  47. Thorne AH, Zanca C, Furnari F. Epidermal growth factor receptor targeting and challenges in glioblastoma. Neuro Oncol. 2016;18:914–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim J, Lee JS, Jung J, Lim I, Lee JY, Park MJ. Emodin suppresses maintenance of stemness by augmenting proteosomal degradation of epidermal growth factor receptor/epidermal growth factor receptor variant III in glioma stem cells. Stem Cells Dev. 2015;24:284–95.

    CAS  PubMed  Google Scholar 

  49. Jahani-Asl A, Yin H, Soleimani VD, Haque T, Luchman HA, Chang NC, et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci. 2016;19:798–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Schmitz M, Temme A, Senner V, Ebner R, Schwind S, Stevanovic S, et al. Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer. 2007;96:1293–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Gangemi RM, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 2009;27:40–48.

    CAS  PubMed  Google Scholar 

  52. Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014;157:580–94.

    PubMed  PubMed Central  Google Scholar 

  53. Ren H, Fu K, Wang D, Mu C, Wang G. Oxidized PARK7 interacts with the mitochondrial protein BCL-XL. J Biol Chem. 2011;286:35308–13537.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Parsanejad M, Zhang Y, Qu D, Irrcher I, Rousseaux MW, Aleyasin H, et al. Regulation of the VHL/HIF-1 pathway by PARK7. J Neurosci. 2014;34:8043–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang S, Mukherjee S, Fan X, Salameh A, Mujoo K, Huang Z, et al. Novel association of PARK7 with HER3 potentiates HER3 activation and signaling in cancer. Oncotarget. 2016;7:65758–69.

    PubMed  PubMed Central  Google Scholar 

  56. Zhou L, Yang H. The Von Hippel-Lindau tumor suppressor protein promotes c-Cbl-independent poly-ubiquitylation and degradation of the activated EGFR. PLoS ONE. 2011;6:e23936.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Cao J, Chen X, Ying M, He Q, Yang B. DJ-1 as a therapeutic target against cancer. Adv Exp Med Biol. 2017;1037:203–22.

    CAS  PubMed  Google Scholar 

  58. Junn E, Jang WH, Zhao X, Jeong BS, Mouradian MM. Mitochondrial localization of DJ-1 leads to enhanced neuroprotection. J Neurosci Res. 2009;87:123–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Canet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA. 2004;101:9103–8.

    PubMed  Google Scholar 

  60. Chen Y, Kang M, Lu W, Guo Q, Zhang B, Xie Q, et al. DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer. J Cancer Res Clin Oncol. 2012;138:1463–74.

    CAS  PubMed  Google Scholar 

  61. Giaime E, Yamaguchi H, Gautier CA, Kitada T, Shen J. Loss of DJ-1 does not affect mitochondrial respiration but increases ROS production and mitochondrial permeability transition pore opening. PLoS ONE. 2012;7:e40501.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by a grant of the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT (MSIT), Republic of Korea. (No. 50531-2019), Nuclear Research and Development Program of the National Research Foundation of Korea (NRF) funded by MSIT, Republic of Korea (No. NRF-2017M2A2A7A02019889), and NRF grant funded by MSIT, Republic of Korea (No. NRF-2019R1A2C2089249).

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Kim, JY., Kim, HJ., Jung, CW. et al. PARK7 maintains the stemness of glioblastoma stem cells by stabilizing epidermal growth factor receptor variant III. Oncogene 40, 508–521 (2021). https://doi.org/10.1038/s41388-020-01543-1

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