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

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 Wang, Bert W. O’Malley () and Zhiqiang Liu ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21386-y

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