Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727297 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14421579_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421579_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421580_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421580_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421581_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 32 |
Similar Datasets
Project description:Cancer stem cells (CSCs) are immature, immortal cells within tumors, adept at resisting therapeutic pressure and responsible for local and distant disease recurrence. Non-genetic mechanisms of acquired resistance are increasingly being described, however molecular insights into this evolutionary process still lack. Here, we showed that Type I interferons (IFNs-I) act as molecular hubs of resistance during immunogenic chemotherapy, as they trigger the epigenetic regulator KDM1B, responsible for an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B pharmacological inhibition antagonizes the appearance of IFN-I-adapted CSCs, both in vitro and in vivo. Notably, IFN-I-adapted CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer patients receiving anthracycline-based chemotherapy, IFN-I and KDM1B signatures positively correlate with CSC and immune evasion markers. Our study identifies IFN-I→KDM1B axis as a potent engine of cancer cell reprogramming and recommends KDM1B targeting an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.
2022-06-30 | GSE173851 | GEO
Project description:Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.
| S-EPMC9477743 | biostudies-literature
Project description:Tumor microenvironment (TME) plays an important role in immune evasion and resistance to immune checkpoint therapy. Here, by using genetic, epigenetic, tumor biology and immunology approaches, we unraveled a key function of KDM1B in TME. KDM1B is important for maintaining several pro-oncogenic cytokine/chemokine signaling pathways. In vivo in resistant and inflammatory breast cancer models, ablation of KDM1B in tumor cells results in increased T cell activity and significantly improved response to anti-PD-1/anti-CTLA-4 therapy. Thus, this study identifies KDM1B as a key regulator of tumor immune microenvironment and offered the mechanistical basis for using KDM1B inhibitors in combinatory therapy to overcome resistance to immune checkpoint blockade.
2021-06-01 | GSE135400 | GEO
Project description:Tumor microenvironment (TME) plays an important role in immune evasion and resistance to immune checkpoint therapy. Here, by using genetic, epigenetic, tumor biology and immunology approaches, we unraveled a key function of KDM1B in TME. KDM1B is important for maintaining several pro-oncogenic cytokine/chemokine signaling pathways. In vivo in resistant and inflammatory breast cancer models, ablation of KDM1B in tumor cells results in increased T cell activity and significantly improved response to anti-PD-1/anti-CTLA-4 therapy. Thus, this study identifies KDM1B as a key regulator of tumor immune microenvironment and offered the mechanistical basis for using KDM1B inhibitors in combinatory therapy to overcome resistance to immune checkpoint blockade.
2021-06-01 | GSE135344 | GEO
Project description:Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with glioma initiating cells (GICs) implicated to be critical for tumor progression and resistance to therapy. KDM1B is involved in regulating GICs' responses to hypoxia, since over-expression of KDM1B delays the cell growth under hypoxia while knocking-down of KDM1B in GICs promotes their survival and tumorigenic abilities.
2015-12-28 | GSE73573 | GEO
Project description:Dynamic histone H3K4 methylation is an important epigenetic component of transcriptional regulation. However, most of our current understanding of this histone mark is confined to regulation of transcriptional initiation. We now show that human LSD2/KDM1b/AOF1, the human homolog of LSD1, is a novel H3K4me1/2 demethylase that specifically regulates histone H3K4 methylation within intragenic regions of its target genes. Genome-wide mapping reveals that LSD2 associates predominantly with the gene bodies of actively transcribed genes, but is markedly absent from promoters. Depletion of endogenous LSD2 results in an increase of H3K4me2 as well as a decrease of H3K9me2 at LSD2 binding sites, and a consequent dysregulation of target gene transcription. Furthermore, characterization of LSD2 complex revealed that LSD2 forms active complexes with euchromatic histone methyltransferases EHMT1/2 and NSD3 as well as cellular factors involved in active transcription elongation. These data provide a possible molecular mechanism linking LSD2 to transcriptional regulation post initiation. We used microarray analysis to identify the subset of genes that are differentially expression after depletion of endogenous LSD2/KDM1b/AOF1. Retroviral shRNA targeting human LSD2 (5â-GTGGGACCACAATGAATTCTT -3â) and control shRNA was used to infect HeLa. RNA was purified 70 hours post infection and processed for Human Genome U133 Plus 2.0 Array (Affymetrix) hybridization per manufactureâs instructions. Biological duplicates were analyzed.
2010-11-01 | E-GEOD-22859 | biostudies-arrayexpress
Project description:Dynamic histone H3K4 methylation is an important epigenetic component of transcriptional regulation. However, most of our current understanding of this histone mark is confined to regulation of transcriptional initiation. We now show that human LSD2/KDM1b/AOF1, the human homolog of LSD1, is a novel H3K4me1/2 demethylase that specifically regulates histone H3K4 methylation within intragenic regions of its target genes. Genome-wide mapping reveals that LSD2 associates predominantly with the gene bodies of actively transcribed genes, but is markedly absent from promoters. Depletion of endogenous LSD2 results in an increase of H3K4me2 as well as a decrease of H3K9me2 at LSD2 binding sites, and a consequent dysregulation of target gene transcription. Furthermore, characterization of LSD2 complex revealed that LSD2 forms active complexes with euchromatic histone methyltransferases EHMT1/2 and NSD3 as well as cellular factors involved in active transcription elongation. These data provide a possible molecular mechanism linking LSD2 to transcriptional regulation post initiation. We used microarray analysis to identify the subset of genes that are differentially expression after depletion of endogenous LSD2/KDM1b/AOF1.
2010-11-01 | GSE22859 | GEO
Project description:Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs.
2017-06-23 | GSE100381 | GEO
Project description:Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs.
2017-06-23 | GSE100382 | GEO
Project description:Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs.
2017-06-23 | GSE100380 | GEO