RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis

• Published in: Experimental & molecular medicine Vol. 50; no. 1; p. e434
• Main Authors: Kim, Wanyeon, Youn, HyeSook, Lee, Sungmin, Kim, EunGi, Kim, Daehoon, Sub Lee, Jung, Lee, Jae-Myung, Youn, BuHyun
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 26.01.2018; Nature Publishing Group
• Subjects: Adult; Aged; Animals; Apoptosis; Apoptosis - radiation effects; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cell Line, Tumor; DNA damage; Female; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - radiotherapy; Glioblastoma cells; Humans; Leukocyte migration; Macrophage migration inhibitory factor; Macrophages; Male; Mice, Inbred BALB C; Middle Aged; Nuclei; Original; Protein Phosphatase 1 - genetics; Radiation Tolerance; Radiation, Ionizing; Radioresistance; Ribosomal protein S3; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; Transcription; Transcription Factor CHOP - metabolism; Ubiquitin; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/emm.2017.247

An interaction between ribosomal protein S3 (rpS3) and nuclear factor kappa B or macrophage migration inhibitory factor in non-small-cell lung cancer is responsible for radioresistance. However, the role of rpS3 in glioblastoma (GBM) has not been investigated to date. Here we found that in irradiated GBM cells, rpS3 translocated into the nucleus and was subsequently ubiquitinated by ring finger protein 138 (RNF138). Ubiquitin-dependent degradation of rpS3 consequently led to radioresistance in GBM cells. To elucidate the apoptotic role of rpS3, we analyzed the interactome of rpS3 in ΔRNF138 GBM cells. Nuclear rpS3 interacted with DNA damage inducible transcript 3 (DDIT3), leading to DDIT3-induced apoptosis in irradiated ΔRNF138 GBM cells. These results were confirmed using in vivo orthotopic xenograft models and GBM patient tissues. This study aims to clarify the role of RNF138 in GBM cells and demonstrate that rpS3 may be a promising substrate of RNF138 for the induction of GBM radioresistance, indicating RNF138 as a potential target for GBM therapy.