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

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.

• Authors: Songwang Xie, Zhen Hong, Yan Li, Junyong Wang, Jian Wang, Shaoquan Li, Yongchang Liu
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 59 Issue 8 Pg. 4703-4717 (Aug 2022) ISSN: 1559-1182 [Electronic] United States
• PMID: 35594003 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Tumor Suppressor Protein p53
• RNF216 protein, human
• RNF216 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Apoptosis
• Brain Neoplasms (genetics)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• DNA Damage
• Gene Expression Regulation, Neoplastic
• Glioblastoma (pathology)
• Humans
• Mice
• Neoplasm Recurrence, Local (genetics)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination