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Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

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  • Jing Liu

    (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)

  • Ying Xie

    (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)

  • Jing Guo

    (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)

  • Xin Li

    (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)

  • Jingjing Wang

    (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)

  • Hongmei Jiang

    (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)

  • Ziyi Peng

    (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)

  • Jingya Wang

    (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)

  • Sheng Wang

    (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)

  • Qian Li

    (Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Tianjin Key Laboratory of Cancer Prevention and Therapy; Tianjin’s Clinical Research Center for Cancer)

  • Linquan Ye

    (Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital)

  • Yuping Zhong

    (Department of Hematology, Myeloma Research Center of Beijing, Beijing Chao-Yang Hospital, Capital Medical University)

  • Qiguo Zhang

    (Department of Hematology, the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School)

  • Xiaozhi Liu

    (Central Laboratory, Tianjin Key Laboratory of Epigenetics for Organ Development of Premature Infants, The Fifth Central Hospital of Tianjin)

  • David M. Lonard

    (Department of Molecular and Cellular Biology, Baylor College of Medicine, Baylor College of Medicine)

  • Jin Wang

    (Department of Pharmacology and Chemical Biology)

  • Bert W. O’Malley

    (Department of Molecular and Cellular Biology, Baylor College of Medicine, Baylor College of Medicine)

  • Zhiqiang Liu

    (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
    Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Tianjin Key Laboratory of Cancer Prevention and Therapy; Tianjin’s Clinical Research Center for Cancer)

Abstract

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

Suggested Citation

  • Jing Liu & Ying Xie & Jing Guo & Xin Li & Jingjing Wang & Hongmei Jiang & Ziyi Peng & Jingya Wang & Sheng Wang & Qian Li & Linquan Ye & Yuping Zhong & Qiguo Zhang & Xiaozhi Liu & David M. Lonard & Jin, 2021. "Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21386-y
    DOI: 10.1038/s41467-021-21386-y
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    Cited by:

    1. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Xiaoquan Wang & Youqiao Wang & Anqi Cao & Qinhong Luo & Daoyuan Chen & Weiqi Zhao & Jun Xu & Qinkai Li & Xianzhang Bu & Junmin Quan, 2023. "Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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