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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 [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

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

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

The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling.

Project description:Senescent cells may possess the intrinsic programs of metabolic and epigenomic remodeling, but the molecular mechanism remains to be clarified. Using an RNAi-based screen of chromatin regulators, we found that knockdown of the NSD2/WHSC1/MMSET methyltransferase induced cellular senescence that augmented mitochondrial mass and oxidative phosphorylation in primary human fibroblasts. Transcriptome analysis showed that loss of NSD2 downregulated the expression of cell cycle-related genes in a retinoblastoma protein (RB)-mediated manner. Chromatin immunoprecipitation analyses further revealed that NSD2 was enriched at the gene bodies of actively transcribed genes, including cell cycle-related genes, and that loss of NSD2 decreased the levels of histone H3 lysine 36 trimethylation (H3K36me3) at these gene loci. Consistent with these findings, oncogene-induced or replicative senescent cells showed reduced NSD2 expression together with lower H3K36me3 levels at NSD2-enriched genes. In addition, we found that NSD2 gene was upregulated by serum stimulation and required for the induction of cell cycle-related genes. Indeed, in both mouse and human tissues and human cancer cell lines, the expression levels of NSD2 were positively correlated with those of cell cycle-related genes. These data reveal that NSD2 plays a pivotal role in epigenomic maintenance and cell cycle control to prevent cellular senescence.

| S-EPMC7433007 | biostudies-literature

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