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

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. Insights into a radiation-resistance mechanism could render a deadly form of brain cancer more amenable to treatment. Glioblastoma multiforme can temporarily be kept in check by chemotherapy and radiotherapy, but most patients succumb to the disease within a year or two of diagnosis. BuHyun Youn and colleagues at Pusan National University, Busan, South Korea, have now discovered that a protein called RFN138 plays a prominent role in the emergence of resistance to treatment. RFN138 chemically modifies another protein, rpS3, in a way that marks it for degradation. Youn's team determined that by eliminating rpS3, RFN138 cripples a cellular pathway that triggers cell death in response to radiation exposure. Analyses of patient samples and mouse models of glioblastoma yielded further evidence linking RFN138 to a worse prognosis. Therapies targeting this protein could lead to better treatment outcomes.