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Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Oncogene volume 41, pages 4971–4979 (2022)Cite this article

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Abstract

The bone marrow microenvironment in multiple myeloma (MM) is hypoxic and provides multi-advantages for the initiation of chemoresistance, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs), and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identified SENP1 as a key modifier of SRC-3 stability, as SENP1-mediated deSUMOylation attenuated the K11-linked polyubiquitination of SRC-3. SENP1 depletion in the SENP1fl/flCD19Cre/+ B cells showed impaired SRC3 stability, and knockdown of SENP1 in MM cells by CRISPR/cas9 sgRNA accelerated the degradation of SRC-3 and remarkably overcame the resistance to PIs. In the Vk*Myc and 5TGM1 mouse models as well as patient-derived xenograft (PDX) of myeloma, SENP1 inhibitor Momordin Ιc (Mc) increased the sensitivity to PIs in MM cells. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our findings suggest that hypoxia-induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.

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Fig. 1: Hypoxia induces Bortezomib resistance in MM cells.
Fig. 2: Hypoxia upregulates SRC-3 level in MM cells.
Fig. 3: Degradation of SRC-3 is ubiquitin-proteasome dependent.
Fig. 4: SENP1 stabilize SRC-3 through deSUMOylation.
Fig. 5: SENP1 is a downstream target of HIF-1α in MM cells.
Fig. 6: SENP1 plays critical role in regulating chemosensitivity to PIs in MM cells.
Fig. 7: Targeting SENP1 in myeloma cells attenuates hypoxia induced SRC-3 expression and drug resistance.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Source data are provided with this paper. Requests for any materials in this study should be directed to Zhiqiang Liu and obtained through an MTA.

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Acknowledgements

This work was supported by Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital. We thank Dr. Leif Bergsagel at the Mayo Clinic for kindly providing the Vk*Myc mouse spleen cells. This work was supported by the Beijing Natural Science Foundation of China (Z200020, ZQL), the National Natural Science Foundation of China (81870161, 82070221, ZQL; 81900215, JYW; 81870150, ZGZ), the Tianjin Research Innovation Project for Postgraduate Students (2020YJSB162, YX), and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A).

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  1. These authors contributed equally: Jing Guo, Yangyang Lv.

Authors and Affiliations

  1. Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, China

    Jing Guo, Yangyang Lv, Zhigang Zhao & Zhiqiang Liu

  2. The province and ministry co-sponsored collaborative innovation center for medical epigenetics; Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases; Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, 300070, China

    Sheng Wang, Ziyi Peng, Ying Xie, Yixuan Wang, Hongmei Jiang, Xin Li, Mengqi Wang, Jingya Wang, Yangyang Xie & Zhiqiang Liu

  3. Tianjin Medical University School of Stomatology, Tianjin Medical University, Heping, Tianjin, 300070, China

    Meilin Hu

  4. Undergarduate School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, 300070, China

    Jiangpeng Mu

  5. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, China

    Xiankui Cheng

  6. Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China

    Zhigang Zhao

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Contributions

LG and ZQL contributed to writing the manuscript; JG, YYL, SW, YX, HMJ, XL, ZY.P., YXW, and JPM contributed to performing the experiments and statistical analyses; JG, SW, MLH, and MQW were in charge of the animal studies; ZGZ and XKC provided the patient samples and clinical statistics; ZQL and ZGZ contributed to the final version of the manuscript.

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Correspondence to Zhigang Zhao or Zhiqiang Liu.

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Guo, J., Lv, Y., Wang, S. et al. Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma. Oncogene 41, 4971–4979 (2022). https://doi.org/10.1038/s41388-022-02494-5

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