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.

TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial–mesenchymal transition

TFAP2C (transcription factor-activating enhancer-binding protein 2C) expression has been positively correlated with poor prognosis in patients with certain types of cancer, but the mechanisms underlying TFAP2C-mediated tumorigenesis in non-small-cell lung cancer (NSCLC) are still unknown. We previously performed a microarray analysis to identify TFAP2C regulation genes, and TGFBR1 (transforming growth factor-β receptor type 1) was found to be upregulated by TFAP2C. We observed that TFAP2C or TGFBR1 overexpression led to oncogenic properties, such as cell viability, proliferation and cell cycle progression. TGFBR1 upregulation induced by TFAP2C also promoted cell motility and migration, leading to malignant development. We also found that PAK1 (p21 protein (Cdc42/Rac)-activated kinase 1) signaling was involved in TFAP2C/TGFBR1-induced tumorigenesis. These results were confirmed by an in vivo xenograft model and patient tissue samples. This study shows that TFAP2C promoted tumor progression by upregulation of TGFBR1 and consequent activation of PAK1 signaling.