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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.

Affiliations

Jeong-Yub Kim  1 , Hee-Jin Kim  1   2 , Chan-Woong Jung  1   3 , Byung-Il Choi  4 , Dea-Hee Lee  5 , Myung-Jin Park  6
1 Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
2 School of Biomedical Science, Korea University, Seoul, Republic of Korea.
3 Department of Life Sciences, Korea University, Seoul, Republic of Korea.
4 Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, Republic of Korea.
5 Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangwon, Republic of Korea. neogene@gwnu.ac.kr.
6 Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. mjpark@kirams.re.kr.