UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2.

ABSTRACT

The key component in the UFM1 conjugation system, UFM1-binding and PCI domain-containing protein 1 (UFBP1), regulates many biological processes. Recently it has been shown that low UFBP1 protein level is associated with the worse outcome of gastric cancer patients. However, how it responses to the sensitivity of gastric cancer to chemotherapy drugs and the underlying molecular mechanism remain elusive. Here, we discovered that high UFBP1 expression increases the progression-free survival of advanced gastric cancer patients treated with platinum-based chemotherapy. Cell-line based studies unveiled that UFBP1 expression enhances while UFBP1 knockdown attenuates the sensitivity of gastric cancer cells to cisplatin. High-throughput SILAC-based quantitative proteomic analysis revealed that the protein level of aldo-keto reductase 1Cs (AKR1Cs) is significantly downregulated by UFBP1. Flow cytometry analysis showed that UFBP1 expression increases while UFBP1 knockdown reduces reactive oxygen species upon cisplatin treatment. We further disclosed that UFBP1 attenuates the gene expression of AKR1Cs and the transcription activity of the master oxidative stress-response transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2). Detailed mechanistic studies manifested that UFBP1 promotes the formation of K48-linked polyubiquitin chains on Nrf2 and thus augments its proteasome-mediated degradation. Experiments using genetic depletion and pharmacological activation in vitro and in vivo demonstrated that UFBP1 enhances the sensitivity of gastric cancer cells to cisplatin through the Nrf2/AKR1C axis. Overall, this work discovered a novel prognostic biomarker for gastric cancer patients treated with platinum-based chemotherapy and elucidated the underlying molecular mechanism, which may benefit to future personalized chemotherapy.