American Association for Cancer Research
10780432ccr191515-sup-221958_3_supp_5962239_q2hgl2.pdf (167.94 kB)

Supplemental Figure S6 from Smoothened Promotes Glioblastoma Radiation Resistance Via Activating USP3-Mediated Claspin Deubiquitination

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journal contribution
posted on 2023-03-31, 21:27 authored by Yiming Tu, Zhenyao Chen, Pengzhan Zhao, Guangchi Sun, Zhongyuan Bao, Honglu Chao, Liang Fan, Chong Li, Yongping You, Yan Qu, Yun Chen, Jing Ji

Supplemental Figure S6


National Natural Science Foundation of China

Jiangsu Province's Natural Science Foundation

Jiangsu Province's Key Discipline of Medicine

Jiangsu Province Medical Key Talent

Jiangsu Provincial Key Research and Development Program



Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance was further confirmed by in vitro and in vivo experiments. We reported that Smo was significantly upregulated in recurrent GBM cell lines and tumor tissues following radiation treatment. Higher Smo expression indicated poor prognosis of GBM patients after radiation treatment. Smo had radioresistance effects in both GBM cells and human tumor xenografts. The mechanisms underlying these effects involved the attenuation of DNA damage repair caused by IR. Importantly, we found that the effect of Smo on radioresistance was mediated by Claspin polyubiquitination and proteasomal degradation, leading to the regulation of ATR–Chk1 signaling. Moreover, we found that Smo reduced Claspin polyubiquitination and proteasomal degradation by promoting USP3 transcription. Furthermore, we demonstrated that the Smo inhibitor GDC-0449 induced radiosensitivity to GBM. These data suggest that Smo confers radiation resistance in GBM by promoting USP3 transcription, leading to the activation of Claspin-dependent ATR–Chk1 signaling. These findings identify a potential mechanism of GBM resistance to radiation and suggest a potential therapeutic target for radiation resistance in GBM.

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