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Endocrine resistance and breast cancer plasticity are controlled by CoREST

ABSTRACT: Using a new model system to track evolution of resistance from ER+ to ER-, we show that the LSD1/CoREST complex is a key determinant for luminal-to-basal reprogramming independently on LSD1’s enzymatic activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168644 | GEO | 2022/08/01

REPOSITORIES: GEO

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Endocrine resistance and breast cancer plasticity are controlled by CoREST

Project description:Endocrine resistance and breast cancer plasticity are controlled by CoREST

| PRJNA713325 | ENA

Endocrine resistance and breast cancer plasticity are controlled by CoREST.

Project description:Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER+ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.

| S-EPMC9707522 | biostudies-literature

Proximity-dependent biotin identification (BioID) reveals a dynamic LSD1-CoREST interactome during embryonic stem cell differentiation

Project description:Lysine specific demethylase 1 (LSD1/KDM1A) regulates gene expression as part of the CoREST complex, along with co-repressor of REST (CoREST) and histone deacetylase 1 (HDAC1). CoREST is recruited to specific genomic loci by components of the core complex and numerous transient interactions with chromatin associated factors and transcription factors. To sample the chromatin environment in proximity to CoREST, we performed proximity-dependent biotin-identification (BioID) with four different members of the complex in 293T cells. Retaining only targets identified with 3 out of 4 baits, we identified 302 CoREST-associated proteins. Among this group were 16 of 18 known CoREST components and numerous novel associations, including readers (CHD3, 4, 6, 7 and 8), writers (KMT2B and KMT2D) and erasers (KDM2B) of histone methylation. However, components of other HDAC1 containing complexes (e.g. Sin3A, NuRD) were largely absent, suggesting that CoREST functions independently. As LSD1 plays an essential role in early embryonic development, we performed BioID using the endogeneously tagged protein in pluripotent, early- and late-differentiating embryonic stem cells. We identified 157 LSD1-associated proteins of which 66 were constitutively associated across all three time-points (44%), including novel interactions with the MMB and ChAHP complexes. These data imply that the majority of CoREST interactions are dynamic and highly cell type dependent.

2021-11-03 | PXD017344 | Pride

CoRest

Project description:Drosophila melanogaster CoRest, CoRest, is differentially expressed in 9 experiment(s);

| FBgn0261573 | ExpressionAtlas

CoRest

Project description:Drosophila melanogaster CoRest, CoRest, is expressed in 4 baseline experiment(s);

| FBgn0261573 | ExpressionAtlas

ZNF516 Is a Potent Suppressor of the EGFR Oncogene through Chromatin Targeting of the CtBP/LSD1/CoREST Complex

Project description:In this study, we report that ZNF516 functions as a transcription repressor. We showed that ZNF516 is physically associated with the CtBP/LSD1/CoREST corepressor complex and transcriptionally represses the expression of a collection of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrated that the ZNF516 inhibits the proliferation and invasive potential of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo. We explored the clinical significance of the ZNF516-CtBP/LSD1/CoREST-EGFR axis in breast carcinomas.

2017-05-01 | GSE97962 | GEO

The chromatin-regulating CoREST complex is animal specific and essential for development in the cnidarian Nematostella vectensis

Project description:Using the sea anemone Nematostella vectensis as a model for early branching metazoans, we show that CoREST is an animal-specific protein that assembles a conserved histone-modifying complex including Lsd1 and HDAC1/2. We further show that the Nematostella complex is similar in composition to vertebrates.

2022-08-08 | PXD033068 | Pride

LSD1 functions through CoREST to maternally reprogram histone methylation

Project description:LSD1 functions through CoREST to maternally reprogram histone methylation

| PRJNA705990 | ENA

The Histone Demethylase LSD1/ZNF217/CoREST Complex is a Major Restriction Factor of Epstein-Barr Virus Lytic Reactivation

Project description:Epstein-Barr virus (EBV) contributes to ~1.5% of human cancers, including lymphomas, gastric and nasopharyngeal carcinomas. In most of these, nearly 80 viral lytic genes are silenced by incompletely understood epigenetic mechanisms, precluding use of antiviral agents such as ganciclovir to treat the 200,000 EBV-associated cancers/year. To identify host factors critical for EBV latency, we performed a human genome-wide CRISPR-Cas9 screen in Burkitt B-cells. Top hits included the lysine-specific histone demethylase LSD1 and its co-repressors ZNF217 and CoREST. LSD1 removes histone 3 lysine 4 (H3K4) and histone 3 lysine 9 (H3K9) methylation marks to downmodulate chromatin activation. LSD1, ZNF217 or CoREST knockout triggered EBV reactivation, as did a LSD1 small molecule antagonist, whose effects were additive with histone deacetylase inhibition. LSD1 blockade reactivated EBV in Burkitt lymphoma, gastric carcinoma and nasopharyngeal carcinoma models, sensitized cells to ganciclovir cytotoxicity and induced EBV reactivation in murine xenografts. ZNF217 and LSD1 co-occupied the EBV immediate early gene BZLF1 promoter, which drives B-cell lytic cycle, as well as to the oriLyt enhancer regions recently implicated in EBV reactivation. LSD1 depletion increased levels of activating histone 3 lysine 4 (H3K4) methylation but not repressive histone lysine 9 methylation marks at BZLF1 and oriLyt and induced their interaction by long-range DNA looping. An orthogonal CRISPR screen highlighted a key H3K4 methyltransferase KMT2D role in driving EBV reactivation. Our results highlight H3K4 methylation as a major EBV lytic switch regulator and suggest novel therapeutic approaches.

2025-02-19 | GSE284859 | GEO

SFMBT1 Functions with LSD1 to Regulate Expression of Canonical Histone Genes and Chromatin-Related Factors [RNA-Seq]

Project description:SFMBT1 is a poorly characterized mammalian MBT domain-containing protein homologous to Drosophila SFMBT, a Polycomb group protein involved in epigenetic regulation of gene expression. Here, we show that SFMBT1 regulates transcription in somatic cells and during spermatogenesis through the formation of a stable complex with LSD1 and CoREST. When bound to its gene targets, SFMBT1 recruits its associated proteins and causes chromatin compaction and transcriptional repression. SFMBT1, LSD1, and CoREST share a large fraction of target genes including those encoding replication-dependent histones. Simultaneous occupancy of histone genes by SFMBT1, LSD1, and CoREST is regulated during the cell cycle and correlates with the loss of RNA polymerase II at these promoters during G2, M, and G1. The interplay between the repressive SFMBT1M-bM-^@M-^SLSD1M-bM-^@M-^SCoREST complex and RNA polymerase II contributes to the timely transcriptional regulation of histone genes in human cells. SFMBT1, LSD1, and CoREST also form a stable complex in germ cells and their chromatin binding activity is regulated during spermatogenesis. RNA-seq in HeLaS3 cells ctrl compared to triple knockdown for SFMBT1, CoREST, and LSD1

2013-03-26 | E-GEOD-45442 | biostudies-arrayexpress

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