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RNF216 Alleviates Radiation-Induced Apoptosis and DNA Damage Through Regulating Ubiquitination-Mediated Degradation of p53 in Glioblastoma

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Abstract

Glioblastoma (GBM) is the most common and lethal subtype of glioma, characterized by uncontrolled cancer cell proliferation, extensive infiltration, and therapeutic resistance. Ring finger protein 216 (RNF216) is a RING-type E3 ubiquitin ligase aberrantly expressed in multiple human cancers. Tumor protein 53 (p53) is a transcription factor that acts as a tumor suppressor. This study aimed to compare the RNF216 expression in GBM tissues and normal peritumoral tissues and to examine the effects of RNF216 overexpression/knockdown on tumorigenesis, radioresistance, and the p53 pathway in GBM. The results showed that RNF216 was overexpressed in GBM tissues and cell lines, and high RNF216 expression was related to a poor prognosis. RNF216 overexpression promoted GBM cell growth and inhibited apoptosis, while RNF216 knockdown impaired GBM cell growth and enhanced cell death. RNF216 was also highly expressed in recurrent GBM tissues compared with paired primary tumors. The upregulation of RNF216 not only facilitated GBM cell growth but also protected cells against X-ray irradiation-induced apoptosis and DNA damage, while RNF216 knockdown exerted opposite effects. Moreover, the implantation of GBM cells with RNF216 silencing suppressed tumorigenesis and increased radiosensitivity of mice bearing GBM xenografts. Further analysis revealed that RNF216 overexpression reduced the stability of p53 protein via ubiquitination and negatively regulated the p53 pathway, while RNF216 knockdown preserved the p53 protein. In conclusion, RNF216 effectively attenuated radiation-induced apoptosis and DNA damage in GBM via inducing ubiquitination-mediated degradation of p53. These findings suggest the potential therapeutic use of RNF216 inhibition for tumorigenesis and therapeutic resistance in GBM.

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All data generated or analyzed during this study are included in this published article.

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Authors and Affiliations

  1. Department of Neurovascular Intervention, Cangzhou Central Hospital, Cangzhou, Hebei, China

    Songwang Xie, Zhen Hong, Yan Li, Junyong Wang, Jian Wang, Shaoquan Li & Yongchang Liu

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  1. Songwang Xie
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  2. Zhen Hong
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  3. Yan Li
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Contributions

Songwang Xie and Zhen Hong designed the study and supervised the data collection; Yan Li and Junyong Wang analyzed the data and interpreted the data; Jian Wang, Shaoquan Li, and Yongchang Liu prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

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Correspondence to Yongchang Liu.

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All procedures performed in studies involving human participants were in accordance with the standards upheld by the Ethics Committee of Cangzhou Central Hospital and with those of the 1964 Helsinki Declaration and its later amendments for ethical research involving human subjects. All animal experiments were approved by the Ethics Committee of Cangzhou Central Hospital for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.

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Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

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Supplementary Information

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Supplementary file 1

The RNF216 expression and survival of GBM patients were analyzed using the CGGA dataset (http://www.cgga.org.cn/). (JPG 6109 KB)

Supplementary file 2

LN229 and A172 cells were treated with 10 µg/mL CHX for 0–60 min. The protein level of p53 at different time points was assessed by Western blot. (JPG 266 KB)

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Xie, S., Hong, Z., Li, Y. et al. RNF216 Alleviates Radiation-Induced Apoptosis and DNA Damage Through Regulating Ubiquitination-Mediated Degradation of p53 in Glioblastoma. Mol Neurobiol 59, 4703–4717 (2022). https://doi.org/10.1007/s12035-022-02868-6

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