Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus supressing TNBC cell proliferation. Finding novel strategies to disrupt BRD4S-LOXL2 interaction holds potential for developing successful TNBC therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198647 | GEO | 2022/03/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

LOXL2 aids the formation of BRD4S and MED1 transcriptional foci to control cell cycle gene expression in triple-negative breast cancer

Project description:LOXL2 aids the formation of BRD4S and MED1 transcriptional foci to control cell cycle gene expression in triple-negative breast cancer

| PRJNA816330 | ENA

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [ChIP-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment

2016-01-07 | E-GEOD-63581 | biostudies-arrayexpress

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [Chem-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)

2016-01-07 | E-GEOD-63284 | biostudies-arrayexpress

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [RNA-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. RNA-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment over time

2016-01-07 | E-GEOD-63582 | biostudies-arrayexpress

ChIP-seq analysis of BRD4, MED1 and P65 in SCC1 cells after JQ1 treatment

Project description:To explore genome-wide alteration of BRD4, MED1, p65 and H3K27Ac during BET inhibition, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of SCC1 cells to examine genome-wide recruitment of the MED1, BRD4, p65 and H3K27ac following JQ1 treatment. BET inhibition by JQ1 led to dramatically loss of the recruitment of MED1, BRD4 and p65 at a cohort of key oncogenes associate with tumorigenesis and metastasis. Suggesting BET inhibition is effective strategy to suppress the tumorigenesis and metastasis of head and neck squamous cell carcinoma.

2021-05-05 | GSE131710 | GEO

LOXL2-mediated chromatin compaction is required to maintain the oncogenic properties of triple-negative breast cancer cells

Project description:Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase–like 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here we show that LOXL2 interacts with RUVBL1, RUVBL2, BAF53, and DMAP1, a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231).

2023-12-31 | GSE142463 | GEO

Med1 overexpression induces cell proliferation

2013-07-18 | GSE48950 | GEO

Med1 overexpression induces cell proliferation

Project description:Med1 overexpression leads to induction of a wide spectrum of genes. Adenovirally-driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control and liver specific genes as observed at day 3 and day 5 post injection. Med1 gene is amplified in a number of cancers so in this study we tested the hypothesis that Med1 by itself has the capacity to induce cell proliferation. Analysis of the Med1- induced gene expression showed a robust induction of a wide spectrum of genes involved in hepatocellular proliferation. Med1 floxed mice (Med1fl/fl) were injected with Ad-His-Med1 (adenovirus expressing Med1 gene) via tail vein and killed 3 or 5 days after injection. Ad-LacZ (adenovirus expression beta-galactosidase gene) injected mouse liver served as control. Total RNA were isolated from the liver and subjected to the microarray.

2013-07-18 | E-GEOD-48950 | biostudies-arrayexpress

LOXL2 dependent genes in RA induced mES differentiation

Project description:Our results indicate that oxidation of TAF10 by LOXL2 induces its release from its promoters, leading to a block in TFIID-dependent gene transcription. Since TFIID complex is crucial for the expression of Nanog, Klf4, Sox2 and Oct4 and for maintaining the pluripotent state of embryonic stem cells, TAF10 oxidation by LOXL2 leads to inactivation of the pluripotency genes and a loss of pluripotent capacity in embryonic stem cells. Moreover, in vivo results demonstrate an essential role of LOXL2 in neural differentiation during zebrafish development: in the absence of LOXL2 the neural progenitor gene Sox2 is aberrantly overexpressed and neural differentiation is impaired. 12 samples were analyzed: mES transduced with control shRNA (n=3); mES transduced with LOXL2 shRNA (n=3), ES transduced with control shRNA and treated with RA (n=3); ES transduced with LOXL2 shRNA and treated with RA (n=3)

2015-12-21 | E-GEOD-65675 | biostudies-arrayexpress

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [RNA-Seq]

2016-01-07 | GSE63582 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data