Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA390904 | ENA |
REPOSITORIES: ENA
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Project description:T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1. Here we describe the anti-cancer effects and mechanism of action of T-3775440 in small cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. Our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC.
2018-02-01 | GSE100169 | GEO
Project description:Small cell lung cancer (SCLC) is characterized by aggressive progression and limited treatment options, necessitating novel therapeutic strategies. Lysine-specific histone demethylase 1A (LSD1), a key epigenetic enzyme essential for maintaining the neuroendocrine phenotype, represses NOTCH and TGF-β signaling. Reactivation of these pathways suppresses proliferation and induces differentiation, underscoring LSD1's potential as a therapeutic target. However, the molecular mechanisms underlying LSD1 inhibition and chemoresistance drivers remain poorly understood. Here, through structure-based engineering, we developed TAS1440, a potent histone H3-competitive LSD1 inhibitor designed to enhance specificity and reduce off-target effects. Unlike covalent inhibitors, which bind irreversibly to the FAD cofactor in LSD1, TAS1440 non-covalently targets the histone H3-binding pocket, improving safety and efficacy. TAS1440 demonstrated superior anti-proliferative activity in SCLC-A cells with high INSM1 and ASCL1 expression. In xenograft models, TAS1440 achieved over 70% tumor growth inhibition with minimal toxicity, highlighting its potential for SCLC. Mechanistically, integrated studies revealed that TAS1440 exerts dual mechanisms: direct inhibition of LSD1 enzymatic activity and disruption of LSD1-repressive complexes, thereby altering the histone modification landscape and activating transcription factors such as INSM1 and SMAD2. These actions coordinately reprogram tumor-suppressive pathways, including TGF-β and NOTCH signaling, positioning TAS1440 as an effective epigenetic therapy for SCLC. Importantly, Loss of LSD1 enzymatic activity and INSM1 knockout abrogated TAS1440’s effects, elucidating its mechanism of action and uncovering potential resistance pathways. These findings establish TAS1440 as a next-generation LSD1 inhibitor with dual actions on transcriptional regulation and epigenetic reprogramming. TAS1440 holds significant promise as a targeted therapy for SCLC, particularly for the SCLC-A subtype with high INSM1 expression.
2026-01-20 | GSE272003 | GEO
Project description:Small cell lung cancer (SCLC) is characterized by aggressive progression and limited treatment options, necessitating novel therapeutic strategies. Lysine-specific histone demethylase 1A (LSD1), a key epigenetic enzyme essential for maintaining the neuroendocrine phenotype, represses NOTCH and TGF-β signaling. Reactivation of these pathways suppresses proliferation and induces differentiation, underscoring LSD1's potential as a therapeutic target. However, the molecular mechanisms underlying LSD1 inhibition and chemoresistance drivers remain poorly understood. Here, through structure-based engineering, we developed TAS1440, a potent histone H3-competitive LSD1 inhibitor designed to enhance specificity and reduce off-target effects. Unlike covalent inhibitors, which bind irreversibly to the FAD cofactor in LSD1, TAS1440 non-covalently targets the histone H3-binding pocket, improving safety and efficacy. TAS1440 demonstrated superior anti-proliferative activity in SCLC-A cells with high INSM1 and ASCL1 expression. In xenograft models, TAS1440 achieved over 70% tumor growth inhibition with minimal toxicity, highlighting its potential for SCLC. Mechanistically, integrated studies revealed that TAS1440 exerts dual mechanisms: direct inhibition of LSD1 enzymatic activity and disruption of LSD1-repressive complexes, thereby altering the histone modification landscape and activating transcription factors such as INSM1 and SMAD2. These actions coordinately reprogram tumor-suppressive pathways, including TGF-β and NOTCH signaling, positioning TAS1440 as an effective epigenetic therapy for SCLC. Importantly, Loss of LSD1 enzymatic activity and INSM1 knockout abrogated TAS1440’s effects, elucidating its mechanism of action and uncovering potential resistance pathways. These findings establish TAS1440 as a next-generation LSD1 inhibitor with dual actions on transcriptional regulation and epigenetic reprogramming. TAS1440 holds significant promise as a targeted therapy for SCLC, particularly for the SCLC-A subtype with high INSM1 expression.
2026-01-20 | GSE272002 | GEO
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To investigate the mechanism of LSD1 efficacy in SCLC cell lines we used chromatin immunoprecipitation (ChIP) sequencing studies to examine the genomic distribution of LSD1 as well as H3K4me2 and H3K4me1 in NCI-H526 SCLC cells in the absence and presence of LSD1 inhibition.
2015-07-14 | E-GEOD-66297 | biostudies-arrayexpress
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. DNA methylation profiling was performed using Infinium 450K methylation arrays on SCLC cell lines, patient derived xenografts, and patient samples. Data was processed and normalized using GenomeStudio V2011.1
2015-07-14 | E-GEOD-66295 | biostudies-arrayexpress
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To gain insight into the mechanism of LSD1 inhibition in inhibiting growth in SCLC cell lines, the effect of GSK2879552 on gene expression was evaluated in 6 SCLC lines, three sensitive to the growth inhibitory effects of GSK2879552 and three resistant. Expression was measured on Affy HG-U133_PLUS_2 microarrays at three time points (2, 4, and 7 days) with replicates.
2015-07-14 | E-GEOD-66294 | biostudies-arrayexpress
Project description:Dominant-negative mutations in transcription factor Growth Factor Independence-1B (GFI1B) cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that normal and mutant GFI1B interacted most strongly with the LSD1-RCOR-HDAC corepressor complex in megakaryoblasts. Sequestration of this complex by mutant GFI1B and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B-mutant induced pluripotent stem cells (iPSC) also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant iPSC-derived megakaryocytes identified a multitude of deregulated pathways downstream of mutant GFI1B. Proteome studies on primary normal and GFI1B-mutant platelets showed reduced expression of proteins implicated in platelet function, and sustained expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B regulates a broad developmental program during megakaryopoiesis. Mutant GFI1B deregulates this program through LSD1-RCOR-HDAC sequestering.
2019-01-25 | PXD009020 | Pride
Project description:How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2â??IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. ChIP-Sequencing profiles of the IRF2BP2, GFI1B and LSD1 proteins were generated using mouse erythroleukemia (MEL) cells. RNA-seq experiments of Irf2bp2-WT, Irf2bp2-KD, Eto2-WT, Eto2-KD, Gfi1b-WT, Gfi1b-KD, Lsd1-WT, Lsd1-KD, MEL-non-induced, and MEL-induced stages were performed using standard RNA-seq protocol. Illumina HiSeq 2000 (standard TruSeq RNA sequencing protocol) was used for the sequencing.
2015-11-19 | E-GEOD-59859 | biostudies-arrayexpress
Project description:In this study we focused on unrevealing the role of major transcriptional factor GFI1B and its cofactor, LSD1 in human endothelial to hematopoietic transition (EHT). We applied irreversible LSD1 inhibitor (GSK-LSD1) to healthy iPSC lines. Interestingly, LSD1 inhibited healthy lines which showed complete absence of hematopoietic cell output, did not showed detection of GFI1B expression, suggesting a timed transcriptional program. In order to test this hypothesis, we ectopically expressed GFI1B in the uncommitted HE cells, leading to downregulation of endothelial genes and an upregulation of hematopoietic genes, including GATA2, KIT, RUNX1 and SPI1.
2024-12-18 | GSE246386 | GEO
Project description:The transcription factor Growth Factor Independence 1B (GFI1B) recruits Lysine Specific Demethylase 1A (LSD1/KDM1A) to stimulate gene programs relevant for megakaryocyte and platelet biology. Inherited pathogenic GFI1B variants result in thrombocytopenia and bleeding propensities with varying intensity. Whether these affect similar gene programs is unknow. Here we studied transcriptomic effects of four patient-derived GFI1B variants (GFI1BT174N,H181Y,R184P,Q287*) in MEG01 megakaryoblasts. Compared to normal GFI1B, each variant affected different gene programs with GFI1BQ287* uniquely failing to repress myeloid traits. In line with this, single cell RNA-sequencing of induced pluripotent stem cell (iPSC)-derived megakaryocytes revealed a 4.5-fold decrease in the megakaryocyte/myeloid cell ratio in GFI1BQ287* versus normal conditions. Inhibiting the GFI1B-LSD1 interaction with small molecule GSK-LSD1 resulted in activation of myeloid genes in normal iPSC-derived megakaryocytes similar as observed for GFI1BQ287* iPSC-derived megakaryocytes. Thus, GFI1B and LSD1 facilitate gene programs relevant for megakaryopoiesis while simultaneously repressing programs that induce myeloid differentiation.
2024-03-28 | PXD050401 | Pride