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Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1

Oncogene volume 41, pages 1298–1308 (2022)Cite this article

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Abstract

Despite the establishment of novel therapeutic interventions, multiple myeloma (MM) remains invariably incurable due to development of drug resistance and subsequent relapse, which are attributed to activation of oncogenic pathways such as autophagy. Deubiquitinating enzymes (DUBs) are promising targets to overcome resistance to proteasome inhibitor-based treatment. Ubiquitin-specific protease-12 (USP12) is a DUB with a known prognostic value in several cancers. We found that USP12 protein levels were significantly higher in myeloma patient samples than in non-cancerous human samples. Depletion of USP12 suppressed cell growth and clonogenicity and inhibited autophagy. Mechanistic studies showed that USP12 interacted with, deubiquitylated and stabilized the critical autophagy mediator HMGB1 (high mobility group box-1) protein. Knockdown of USP12 decreased the level of HMGB1 and suppressed HMGB1-mediated autophagy in MM. Furthermore, basal autophagy activity associated with USP12/HMGB1 was elevated in bortezomib (BTZ)-resistant MM cell lines. USP12 depletion, concomitant with a reduced expression of HMGB1, suppressed autophagy and increased the sensitivity of resistant cells to BTZ. Collectively, our findings have identified an important role of the deubiquitylase USP12 in pro-survival autophagy and resultant BTZ resistance in MM by stabilizing HMGB1, suggesting that the USP12/HMGB1 axis might be pursued as a potential diagnostic and therapeutic target in human MM.

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Fig. 1: USP12 confers MM cells growth and survival.
Fig. 2: USP12 enhances tumorigenicity of myeloma xenograft.
Fig. 3: USP12 depletion inhibits autophagy in MM.
Fig. 4: USP12 interacts with HMGB1.
Fig. 5: USP12 induces autophagy by stabilizing the protein level of HMGB1.
Fig. 6: USP12/HMGB1 mediated autophagy enhances the BTZ resistance of MM cells.
Fig. 7: USP12 stabilizes HMGB1 to promote survival of MM.

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Funding

This study was supported by grants from the National Key Research and Development Program of China (2018YFA0107800), the National Natural Science Foundation of China (Nos. 21890744, 81672760, 82003286, 81970195, 81920108004, 81772496 and 82073099), the Natural Science Foundation of Hunan Province (No. 2021JJ40054, 2019JJ40391), the China Postdoctoral Science Foundation (2020M672474, 2021T140195 and 2018M630896), the Hunan Provincial Key Research and Development Plan (2018SK2128), the Changsha Municipal Natural Science Foundation (kq2014041, kq2014042 and kq2001012).

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  1. These authors contributed equally: Hui Li, Mridul Roy.

Authors and Affiliations

  1. Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, Hunan, 410082, China

    Hui Li, Mridul Roy & Mao Ye

  2. Molecular Biology Research Center, Center for Medical Genetics, Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, 410078, China

    Hui Li, Mridul Roy, Bin Hu, Yanan Li, Xiaojuan Xiao, Haiqin Wang, Shuming Sun & Jing Liu

  3. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Hui Li & Long Liang

  4. Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, China

    Wenjie Cao & Bin Zhang

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Contributions

HL and MR contributed equally to this work. JL, BZ, MY and SS designed the research, HL, MR, LL, WC, BH, YL, XX and HW performed the experiments, analyzed and interpreted the data; BZ, SS, MY and JL analyzed and interpreted the data; MR, HL, JL and MY drafted and revised the manuscript.

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Correspondence to Mao Ye, Shuming Sun, Bin Zhang or Jing Liu.

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Li, H., Roy, M., Liang, L. et al. Deubiquitylase USP12 induces pro-survival autophagy and bortezomib resistance in multiple myeloma by stabilizing HMGB1. Oncogene 41, 1298–1308 (2022). https://doi.org/10.1038/s41388-021-02167-9

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