SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163682 | GEO | 2021/12/31
REPOSITORIES: GEO
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Project description:Sumoylation is a post-translational modification process that is deregulated in cancer. We foundthat sumoylation machinery was overexpressed in diffuse large B-cell lymphoma (DLBCL).Treatment with TAK-981, a SUMO-activating enzyme (SAE) inhibitor, induced desumoylationof cytoplasmic and mitochondrial proteins, restricting growth of DLBCL and mantle celllymphoma (MCL) cell lines and primary cells. DLBCL cells treated with TAK-981 exhibitedDNA damage, G2 arrest and downregulation of DNA repair, MYC and OxPhos pathways. SAEinhibition disrupted mitochondrial integrity and function, accompanied by mitophagy and rapidaccumulation of ROS. Metabolomic profiling revealed decreases in Krebs cycle substrates, andSeahorse respirometry confirmed dramatic reduction in OxPhos upon SAE inhibition. CRISPR-Cas9 loss-of-function library screens implicated NFκB, TP53, DNA damage andcentromere/telomere gene pathways in resistance to SAE inhibition; knockout of TP53 or BAXrescued DLBCL cells from TAK-981-induced apoptosis. Treatment with TAK-981 prolongedsurvival of mice xenografted with DLBCL and MCL PDX tumors. Thus, sumoylation is apromising target in lymphoid malignancies.
2024-02-02 | GSE254913 | GEO
Project description:SUMOylation, a post-translational modification of the ubiquitin family plays a critical role in the regulation of proteins function and fate. TAK-981 (Subasumstat) is a first-in-class inhibitor of the SUMO-activating enzyme used in various phase I/II clinical trials for solid tumors and lymphomas. In addition to its direct cytotoxic effect on cancer cells, TAK-981 activates anti-tumor immune response. We show here that TAK-981 activates human natural killer cells. TAK-981 mostly regulates genes involved in inflammation and immune response, in particular those related to the type-I and type-II interferon pathway.
2024-02-28 | GSE255279 | GEO
Project description:The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.
2022-01-10 | PXD024521 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activating enzyme E1 (SAE) could be used to treat a preclinical syngeneic PDAC mouse model. We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared to normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumor burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and NK cells but transiently decreased B cell numbers in peripheral blood, spleen and lymph nodes. ScRNA sequencing revealed activation of the interferon response upon TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumor immunity by inducing interferon signaling.
2022-01-11 | GSE189576 | GEO
Project description:Acute Myeloid Leukemias (AML) are severe hematomalignancies with dismal prognosis. The post-translational modification SUMOylation plays key roles in leukemogenesis and AML response to therapies. Here, we show that TAK-981 (subasumstat), a first-in-class SUMOylation inhibitor, is endowed with potent anti-leukemic activity in various preclinical models of AML. TAK-981 targets AML cell lines and patient blast cells in vitro and in vivo in xenografted mice with minimal toxicity on normal hematopoietic cells. Moreover, it synergizes with 5-azacitidine (AZA), a DNA-hypomethylating agent now used in combination with the BCL-2 inhibitor venetoclax to treat AML patients unfit for standard chemotherapies. Interestingly, TAK-981+AZA combination shows higher anti-leukemic activity than AZA+venetoclax combination both in vitro and in vivo, at least in the models tested. Mechanistically, TAK-981 potentiates the transcriptional reprogramming induced by AZA, promoting apoptosis, alteration of the cell cycle and differentiation of the leukemic cells. In addition, TAK-981+AZA treatment induces many genes linked to inflammation and immune response pathways. In particular, this leads to the secretion of type I interferon (IFN-I) by AML cells. Finally, TAK-981+AZA induces the expression of Natural Killer (NK)-activating ligands (MICA/B) and adhesion proteins (ICAM-1) at the surface of AML cells. Consistently, TAK-981+AZA-treated AML cells activate NKs and increase their cytotoxic activity. Targeting SUMOylation with TAK-981 may thus be a promising strategy to both sensitize AML cells to AZA and reduce their immune-escape capacities.
2023-08-29 | GSE212330 | GEO
Project description:Small ubiquitin-like modifier (SUMO) family proteins regulate target protein functions by post-translational modification. However, a potent and selective inhibitor to target the SUMO pathway has been lacking. Here we describe ML-792, the first mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, which leads to reduced cancer cell proliferation. Moreover, induction of the MYC oncogene increased the ML-792 mediated viability effect in cancer cells, indicating potential application of SAE inhibitors in MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic subunit (UBA2) mutant S95N/M97T rescued SUMOylation loss and the mitotic defect induced by ML-792, confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins allowing for novel insights into SUMO biology.
2017-09-01 | GSE100408 | GEO
Project description:SUMOylation, a posttranslational modification, regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use ML-792, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in macrophages derived from bone marrow of C57BL/6 mice. Mouse bone marrow cells isolated from 6–10 weeks C57BL/6 mice were cultured in IMDM medium supplemented with 10% (vol/vol) FBS and 10 ng/mL of macrophage colony-stimulating factor (M-CSF). After 6–8 days of differentiation, the cells were treated with vehicle or ML-792 at 0.5 μM for 24 h. Total RNA was purified using miRNeasy RNA isolation kit (Qiagen) then Ribo-Zero RNA-seq was performed.
2023-10-05 | GSE217604 | GEO
Project description:SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor TAK-981 in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated synergistic antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.
2024-04-24 | GSE185841 | GEO
Project description:We examine how SUMO post-translational modification of the yeast transcription factor Sko1 affects its binding site selection and affinity. Chromatin immunoprecipitation followed by next-generation sequencing was performed in strains expressing wild-type Sko1 (Sko1-WT) or Sko1 that harbors an Arg-to-Lys mutation at Lys 567 (Sko1-MT), that impairs its sumoylation. We find that, compared with Sko1-WT, SUMO-deficient Sko1 binds numerous additional sites that are near promoters of non-Sko1 target genes. Furthermore, Sko1-MT shows higher occupancy levels than Sko1-WT on most genes that are occupied by both forms. Osmotic stress causes a general rearrangement of Sko1 positions across the genome, but increased numbers of binding sites and occupancy levels are still observed for Sko1-MT after treatment with NaCl. This study indicates that sumoylation attenuates Sko1 association with chromatin and increases its binding specificity.
2019-02-04 | GSE118655 | GEO
Project description:Many transcription-related proteins, including components of the RNA polymerase II (RNAPII) general transcription factors (GTFs), have been shown through proteomics studies to be modifiable by SUMO conjugation. However, we determined that the large subunit of TFIIF, Tfg1, is likely the major target of sumoylation among GTFs in budding yeast. The primary site of sumoylation on Tfg1 is Lys residues 60 or 61, which lies in a region of the protein that is proximal to the Rpb2 subunit of RNAPII when the GTF-RNAPII preinitiation complex (PIC) assembles at promoters. As TFIIF and RNAPII are highly functionally and physically linked, we examined whether blocking Tfg1 sumoylation through Lys-to-Arg mutations could affect the recruitment or association of RNAPII with chromatin. RNAPII ChIP-seq was performed in strains expressing wild-type (Tfg1-HA) or sumoylation-deficient (Tfg1-K60,61R-HA) forms of Tfg1. Indeed, nearly half of all protein-coding genes showed significantly reduced RNAPII levels in the mutant strain. These data suggest that sumoylation of TFIIF plays an important role in regulating the dynamics of RNAPII association with genes.
2021-09-21 | GSE167426 | GEO