Abstract

Proteasome inhibitors are approved to treat multiple myeloma and mantle cell lymphoma. Recent reports suggest sarcomas also display proteasome addiction. Mechanistic explanations cite proteotoxic stress. In sarcoma patients, we analyzed the impacts of 377 human E3 ubiquitin ligases on sarcoma patient overall survival (OS) and recurrence-free survival (RFS), identified substrates of E3 ligases with the most significant and robust effects, and performed enrichment analyses. High expression of 102 E3 ligases was associated with shortened OS. Thirteen of these shortened OS by >40 months, six with false-discovery rates (FDR) ≤ 5%. Nineteen showed correlation between increased expression and shortened RFS, two with FDR ≤ 5%. Overexpression of 73 E3 ligases significantly extended OS, with 18 extending OS by >40 months; six with FDR ≤ 5%. Elevated expression of 21 significantly extended RFS, one with FDR ≤ 5%. Enrichment analyses of substrates unique to the E3 ligases whose elevated expression most reliably shortened or extended OS by >40 months revealed non-overlapping functions: the E3 ligases associated with shortened OS uniquely targeted cell cycle, cell–cell communication, cellular responses to stimuli, chromatin organization, DNA repair, DNA replication, hemostasis, reproduction, and vesicle-mediated transport functions. Both OS-impacting E3 ligase sets targeted developmental biology, gene expression, immune system, metabolism of proteins, and signal transduction functions. Three specific functions were targeted by both groups. Functions uniquely targeted by each set of ligases could reveal therapeutic targets with a greater therapeutic index than the proteasome.

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