Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors

• Main Authors: Xiaowen Wang, Matias A. Bustos, Xiaoqing Zhang, Romela Irene Ramos, Cong Tan, Yuuki Iida, Shu-Ching Chang, Matthew P. Salomon, Kevin Tran, Rebecca Gentry, Yelena Kravtsova-Ivantsiv, Daniel F. Kelly, Gordon B. Mills, Aaron Ciechanover, Ying Mao, Dave S.B. Hoon
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: Cancers
• Subjects: p50; miR-155; PAI-1; KPC1; NF-κB pathway
• Online Access: https://www.mdpi.com/2072-6694/12/5/1081

This study examined the role of the ubiquitin E3-ligase RNF123 in modulating downstream NF-κB1 targets in glioblastoma (GB) tumor progression. Our findings revealed an oncogenic pathway (miR-155-5p-RNF123-NF-κB1-p50-SerpinE1) that may represent a new therapeutic target pathway for GB patients with isocitrate dehydrogenase 1 and 2 (<i>IDH</i>) WT (wild type). Mechanistically, we demonstrated that <i>RNF123</i> is downregulated in <i>IDH</i> WT GB patients and leads to the reduction of p50 levels. RNA-sequencing, reverse-phase protein arrays, and in vitro functional assays on <i>IDH</i> WT GB cell lines with RNF123 overexpression showed that SerpinE1 was a downstream target that is negatively regulated by RNF123. <i>SERPINE1</i> knockdown reduced the proliferation and invasion of <i>IDH</i> WT GB cell lines. Both SerpinE1 and miR-155-5p overexpression negatively modulated RNF123 expression. In clinical translational analysis, RNF123, SerpinE1, and miR-155-5p were all associated with poor outcomes in GB patients. Multivariable analysis in <i>IDH</i> WT GB patients showed that concurrent low RNF123 and high SerpinE1 was an independent prognostic factor in predicting poor overall survival (<i>p</i> < 0.001, hazard ratio (HR) = 2.93, 95% confidence interval (CI) 1.7–5.05), and an increased risk of recurrence (<i>p</i> < 0.001, relative risk (RR) = 3.56, 95% CI 1.61–7.83).