Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA352778 | ENA |
REPOSITORIES: ENA
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Project description:Lysine-specific demethylase 1A (LSD1) specifically demethylates di- and monomethylated histone H3K4 or K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models.The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation and suppression of the leukemic stem cell gene signature.
2017-06-30 | GSE89637 | 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 transcriptional profile of the human multiple myeloma (MM) cell line MM.1S treated with MLN4924 vs control MM.1S cells was characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip, according to previously described protocols for total RNA extraction and purification; cDNA synthesis; in vitro transcription reaction for production of biotin-labeled cRNA; hybridization of cRNA with U133plus2.0 Affymetrix gene chips; and scanning of image output files. Scanned image output files were analyzed using DNA-Chip Analyzer (dChip) (www.dchip.org), including conversion to DCP files, normalization and modeling. The gene expression profile of MM.1S cells for each time point of MLN4924 treatment was compared to the profile of control MM.1S cells. The NEDD8 activating enzyme (NAE) is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases (CRLs), which regulate degradation of a distinct subset of proteins. The more targeted impact of NAE on protein degradation prompted us to study MLN4924, an investigational NAE inhibitor, in preclinical multiple myeloma (MM) models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability in a panel of human MM cell lines. In this analysis, we evaluated the molecular changes triggered in MM.1S myeloma cells by their in vitro treatment with MLN4924. The transcriptional profiles of each experimental condition were characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip. The human multiple myeloma (MM) cells MM.1S were cultured in vitro in the presence or absence of the NEDD8 activating enzyme (NAE) inhibitor MLN4924 for 8, 16 or 24hrs. The gene expression profiles of drug treated cells were compared with the profiles of control MM.1S cells.
2012-05-01 | E-GEOD-33577 | biostudies-arrayexpress
Project description:MLN4924, also known as pevonedistat, is a small molecule inhibitor of NEDD8 activating enzyme (NAE), that inhibits the entire neddylation pathway. As the first-in-class neddylation inhibitor, MLN4924 is currently in Phase I/II clinical trials for anticancer application as a single agent or in combination with chemotherapeutic drugs. MLN4924 has shown impressive anticancer activity by inactivating Cullin-RING ligases (CRLs) to cause accumulation of tumor suppressor substrates. Whether MLN4924 regulates the RNA expression by modulating the levels of transcription factor/repressor remain elusive. In this study, we treated A549 lung cancer cells with MLN4924 at 0.25 or 0.5 µM for 8 or 24 hrs, respectively, followed by RNAseq analysis. Here we found that MLN4924 significantly decreases the SOX2 mRNA level. The mechanistic study revealed that MLN4924 inhibits FBXW2 E3 to cause MSX2 accumulation, which in turn transcriptionally represses SOX2, leading to suppression of stem cell property and sensitization of cancer cells to tamoxifen.
2019-09-14 | GSE134190 | GEO
Project description:TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 (UBA1) that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase 1 clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243
2021-01-13 | GSE164639 | GEO
Project description:Resistance to proteasome inhibitors has prompted interest in blocking upstream components of the ubiquitin-proteasome pathway for the treatment of multiple myeloma (MM). We therefore evaluated the activity of TAK-243, a novel and specific inhibitor of E1 ubiquitin activating enzyme (UAE) activity, in the MM cell line MM1.S. Treatment of MM1.S with 25 nM TAK-243 for 24 hr caused extensive changes in gene expression, highly uniform between triplicates.
2019-05-01 | GSE126254 | GEO
Project description:SUMOylation, a posttranslational modification, regulates proteins by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in glucocorticoid sensitive and resistant multiple myeloma cell lines.
2021-12-31 | GSE163682 | 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:We investigated the combination of the irreversible LSD1 inhibitor T-3775440 and the JAK1/JAK2 inhibitor ruxolitinib as novel therapeutic approach in ML-DS which is specifically designed to target key hallmarks of ML-DS leukemogenesis. We observed synergistic anti-leukemic effects by combining both drugs. To elucidate the underlying molecular mechanisms we performed RNAseq in two independent patients samples treated with vehicle, LSD1 inhibitor or ruxolitinib monotherapy or the combination of both drugs.
2022-05-27 | GSE201093 | GEO
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