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

Oncogene volume 40, pages 508–521 (2021)Cite this article

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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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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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  1. These authors contributed equally: Jeong-Yub Kim, Hee-Jin Kim

Authors and Affiliations

  1. Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

    Jeong-Yub Kim, Hee-Jin Kim, Chan-Woong Jung & Myung-Jin Park

  2. School of Biomedical Science, Korea University, Seoul, Republic of Korea

    Hee-Jin Kim

  3. Department of Life Sciences, Korea University, Seoul, Republic of Korea

    Chan-Woong Jung

  4. Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, Republic of Korea

    Byung-Il Choi

  5. Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangwon, Republic of Korea

    Dae-Hee Lee

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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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