RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ

Abstract

Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue–based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.

The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation

“…As one of RBPJ’s target genes is often mutated in glioma, its downregulation diminished the malignant phenotype [ 40 ]. Similarly, in bladder cancer cells, overexpressed RITA1 induced degradation of RBPJ by recruiting the E3 ligase TRIM25 [ 80 ]. In this case, however, RBPJ proteolysis appeared to increase malignancy, which may apply for other cancer types linked to TRIM25 activity as well [ 80 , 81 , 82 , 83 ].…”

“…We favour the idea, however, that further cofactors present in HeLa cells prevented Rbpj proteolysis. The many possible interaction partners would easily explain the remarkable stability of mammalian CSL protein, as well as the drastic differences in half-life measurements [ 38 , 39 , 40 , 80 ]. Interestingly, the opposite mechanism was discovered for human Notch1 [ 91 ].…”

E3 ubiquitin ligases and deubiquitinases in bladder cancer tumorigenesis and implications for immunotherapies

“…Bladder cancer patients with low ANXA2 expression and high TRIM65 expression showed the poorest outcome ( 53 ). RITA1 recruits TRIM25 to ubiquitinate RBPJ to accelerate its degradation via the proteasome, which leads to transcriptional inhibition of Notch1 downstream targets ( 54 ). TRIM26 plays an oncogenic role in bladder cancer by regulating cell proliferation, migration, and invasion via the AKT/GSK3β/β-catenin pathway ( 55 ).…”