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

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.

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

“…Herein we reveal that MDC1 acts as a scaffold for Recently, ample researches have highlighted the importance of protein condensations, such as liquid-liquid phase separation (LLPS), in physiological and pathophysiological processes 26,27 . Our previous study also reported the LLPS of SRC-3 in mediating drug resistance to PIs in MM cell 19 . The acetylation and deacetylation of IDRs regulate LLPS spatiotemporally and impact membrane-less organelle formation in vivo 28 .…”

“…7G). In addition, using an intra-bone growing MM model established in our laboratory 19 , which can mimic the real bone microenvironment in MM patients, we treated the mice with BTZ solely or together with Rom after 2 weeks of inoculation, and found that the Rom-BTZ combination effectively alleviated bone lesion of mice destroyed by MM cells (Fig. 7K), as evidenced by a smaller size of trabecula separation at the metaphysis and diaphysis (Fig.…”

“…Our previous study demonstrated that interaction with partner proteins enhances the LLPS property of the master protein 19 , and post-translational modifications play critical roles in regulating the LLPS 20,21 . To clarify the relationship between interaction with MDC1 and nuclear condensation of HP1γ, we first evaluated the possibility of LLPS in MDC1 protein, and found that this protein has at least three putative IDR regions (Fig.…”

SRC-3, a Steroid Receptor Coactivator: Implication in Cancer

“…However, the mechanism by which SRC-3 regulates the progression of these cancers has not been further elucidated. Recent study presented that overexpression of SRC-3 was correlated with poor outcome of multiple myeloma patients [ 153 ]. SRC-3 interacted with histone methyltransferase NSD2 and enhanced its liquid–liquid phase separation, thereby altered the transcriptome to compromise the sensitivity of myeloma cells to bortezomib treatment [ 153 ].…”

“…Based on toxicity assay, no acute or chronic toxicity of SI-2 was observed in vivo. Therefore, SI-2 is considered as a highly promising inhibitor for SRC-3 and high potential candidate for developing an anti-cancer drug [ 52 , 118 , 153 , 164 , 165 , 166 , 167 , 168 ]. Besides identifying chemicals used to block the activity of SRC-3, recent studies have also developed new methods for targeting SRC-3.…”