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

Oncogene volume 40, pages 647–662 (2021)Cite this article

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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.

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Fig. 1: UFBP1 enhances the sensitivity of gastric cancer to cisplatin (CDDP).
Fig. 2: UFBP1 downregulates AKR1C1/2/3 and enhances oxidative reduction process in the gastric cancer cells.
Fig. 3: UFBP1 downregulates AKR1C protein and mRNA levels and Nrf2 protein level.
Fig. 4: UFBP1 promotes Nrf2 degradation through the ubiquitin-proteasome system.
Fig. 5: UFBP1 enhances the sensitivity of gastric cancer cells to cisplatin through Nrf2/AKR1C axis.
Fig. 6: Nrf2/AKR1C axis mediates the UFBP1-enhanced sensitivity of gastric cancer cells to cisplatin in xenograft mouse model.

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Data availability

Additional Materials and methods were provided in the Supplementary Materials. The proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [43] partner repository with the dataset identifier PXD013590.

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Acknowledgements

We are grateful to Drs. Xinliang Mao (Soochow University) and Siwang Yu (Peking University) for kindly providing plasmids and to Dr. Guanghui Wang (Soochow University) for fruitful discussion. MS analyses were performed at the Mass Spectrometry core facility of the Medical School of Soochow University. This work was supported by the National Key R&D Program of China (2019YFA0802400), the National Natural Science Foundation of China (31700722 & 31971353), Suzhou Bureau of Science and Technology (Basic Research in Medical and Health Sciences, SYS201718), Talent Program in Six Major Disciplines in Jiangsu Province (SWYY-080), Open Project of Jiangsu Key Laboratory of Neuropsychiatric Diseases (KIS1722), Open Project Program of the State Key Laboratory of Proteomics (SKLP-O201905), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_2040), Natural Science Foundation of Jiangsu Higher Education Institutes of China (17KJA180010), National Center for International Research (2017B01012), a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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  1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, China

    Zhanhong Hu, Xiaohui Wang, Dan Li, Lindong Cao & Guoqiang Xu

  2. Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China

    Zhanhong Hu

  3. Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China

    Hongxia Cui

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ZH and GX conceived and designed the experiments; ZH, XW, DL, LC, and HC performed the experiments and analyzed the data; ZH and GX wrote the paper; all authors revised the paper.

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Correspondence to Guoqiang Xu.

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Hu, Z., Wang, X., Li, D. et al. UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2. Oncogene 40, 647–662 (2021). https://doi.org/10.1038/s41388-020-01551-1

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