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Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156872 | GEO | 2020/08/26

REPOSITORIES: GEO

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Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [RNA-Seq]

Project description:Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that some drug resistant genes were activated during myeloma resistant to bortezomib. Mechanistically, NSD2 can interact with SRC-3, its SET domain is responsible to H3K36me2 to enhance the transcriptional activity of SRC-3 target gene. The inhibitor of SRC-3, SI-2, can impaired the interaction between NSD2 and SRC-3, caused the distribution of H3K36me2 changed on the genome-wide, and inhibit the transcription of those drug resistant genes.

2020-08-26 | GSE156871 | GEO

Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [ChIP-Seq]

Project description:Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that NSD2/SRC-3 complex coordinates histone H3 lysine 36 dimethylation (H3K36me2) and transcriptional elongation factor Pol II to regulate chromatin dynamic and gene transcription during myeloma resistant to bortezomib. Mechanistically, NSD2 can interact with SRC-3, its SET domain is responsible to H3K36me2 to enhance the transcriptional activity of SRC-3 target gene. The inhibitor of SRC-3, SI-2, can impaired the interaction between NSD2 and SRC-3, caused the distribution of H3K36me2 on the genome-wide.

2020-08-26 | GSE156870 | GEO

Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling

Project description:Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling

| PRJNA659271 | ENA

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

Project description: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.

| S-EPMC7884723 | biostudies-literature

Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [ChIP-Seq]

Project description:Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [ChIP-Seq]

| PRJNA659375 | ENA

Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [RNA-Seq]

Project description:Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [RNA-Seq]

| PRJNA659376 | ENA

All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma.

Project description:BackgroundImmunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored.MethodsThe efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl /SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging.ResultsWe report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo.ConclusionThis study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now.

| S-EPMC10016253 | biostudies-literature

An inhibitor of proteasome ?2 sites sensitizes myeloma cells to immunoproteasome inhibitors.

Project description:Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue-specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, ?5i, ?1i, and ?2i, which are different from their constitutive ?5c, ?1c, and ?2c counterparts. Bortezomib and carfilzomib block ?5c and ?5i sites. We report here that pharmacologically relevant concentrations of ?5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-? increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of ?2 sites, dramatically sensitizes MM cell lines and primary cells to ONX-0914. ONX-0914 synergizes with all FDA-approved proteasome inhibitors in MM in vitro and in vivo. Thus, immunoproteasome inhibitors, currently in clinical trials for the treatment of autoimmune diseases, should also be considered for the treatment of MM.

| S-EPMC6177641 | biostudies-literature

Downregulation of PA28? induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma

Project description:Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28? is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28? also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28? inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28? in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.

| S-EPMC7736847 | biostudies-literature

Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib.

Project description:Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells.

| S-EPMC3134264 | biostudies-literature

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