Targeting NSD2-Mediated SRC-3 Liquid-Liquid Phase Separation Sensitizes Bortezomib Treatment in Multiple Myeloma

Authors

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
Zhiqiang Liu

Publication Date

2-15-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-21386-y

PMID

33589584

PMCID

PMC7884723

PubMedCentral® Posted Date

2-15-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Apoptosis, Bone and Bones, Bortezomib, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 4, Drug Resistance, Neoplasm, Enzyme Inhibitors, Female, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase, Histones, Humans, Male, Middle Aged, Multiple Myeloma, Nuclear Receptor Coactivator 3, Proteasome Inhibitors, Recurrence, Repressor Proteins, Signal Transduction, Survival Analysis, Translocation, Genetic, Xenograft Model Antitumor Assays, Haematological cancer, Myeloma, Chromatin, Chromatin remodelling, Epigenetics

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.

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