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Updated: Nov 17, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma
Jing Liu1, Ying Xie1, Jing Guo1
1The 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, China.
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.
Insights
High steroid receptor coactivator-3 (SRC-3) expression drives chemoresistance in multiple myeloma (MM) by interacting with NSD2. Targeting this interaction with SI-2 overcomes drug resistance, offering a new therapeutic strategy for MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Chemoresistance is a major challenge in multiple myeloma (MM) treatment, leading to therapeutic failure.
- The specific genetic and epigenetic factors contributing to MM chemoresistance are not fully understood.
Purpose of the Study:
- To investigate the role of steroid receptor coactivator-3 (SRC-3) in mediating chemoresistance in multiple myeloma (MM).
- To elucidate the interaction between SRC-3 and histone methyltransferase NSD2 in the context of drug resistance.
- To evaluate the therapeutic potential of targeting the SRC-3/NSD2 interaction in MM.
Main Methods:
- Correlation analysis of SRC-3 expression with clinical outcomes in MM patients treated with bortezomib (BTZ).
- In vitro studies using immortalized cell lines to assess the effect of high SRC-3 on proteasome inhibitor (PI)-induced apoptosis.
- Investigation of NSD2's role in regulating SRC-3 expression and histone modifications (H3K36me2) in BTZ-resistant MM cells.
- In vitro and in vivo evaluation of a novel inhibitor (SI-2) targeting the SRC-3/NSD2 interaction.
Main Results:
- High SRC-3 expression is linked to relapse/refractory disease and poor outcomes in MM patients receiving BTZ-based therapy.
- Elevated SRC-3 enhances resistance to PI-induced apoptosis in MM cell lines.
- Overexpressed NSD2 promotes SRC-3 elevation and H3K36me2 modifications on anti-apoptotic gene promoters, contributing to drug resistance.
- The inhibitor SI-2 effectively sensitizes MM cells to BTZ and overcomes drug resistance in vitro and in vivo.
Conclusions:
- SRC-3 and NSD2 cooperate to drive acquired drug resistance in multiple myeloma (MM).
- Targeting the SRC-3/NSD2 interaction with SI-2 represents a promising strategy to overcome bortezomib resistance in MM.
- These findings identify a novel therapeutic target and approach for improving MM treatment outcomes.
