Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comparison of transcriptomes of PARP inhibitor-treated and -untreated isogenic human BRCA-wildtype ovarian cancer PDX

ABSTRACT: Background: PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC. Results: Using mass spectrometry profiling of histone modifications, we observed altered H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance. Conclusions: This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins such as PCAF, or accessory proteins such as BRPF3, may play a greater role in PARPi response than acetyltransferase functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE191231 | GEO | 2021/12/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

AKT1 interacts with DHX9 to mitigate R-loop-induced replication stress in ovarian cancer

Project description:PARP inhibitor (PARPi)-resistant BRCA mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Quantitative high-throughput drug combination screen identifies that ATR inhibitor (ATRi) and AKT inhibitor (AKTi) combination is a rational treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC by inducing DNA damage and R-loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacts with DHX9, thus facilitating recruitment of DHX9 to R-loops. AKTi increases ATRi-induced R-loop-mediated RS by mitigating recruitment of DHX9 to R-loops. Moreover, DHX9 is upregulated in tumors from PARPi-resistant BRCAm HGSOC patients and high co-expression of DHX9 and AKT1 correlates with worse survival. Our study reveals a previously unknown interaction between AKT1 and DHX9 in R-loop resolution and novel mechanisms of action of AKTi and ATRi combination. Our data also provide a rationale for the clinical development of ATRi and AKTi combination for BRCAm HGSOC irrespective of PARPi resistance status and a potential biomarker to predict the response of combination therapy.

2024-01-10 | GSE252610 | GEO

PCAF/GCN5-regulated genes in MEFs

Project description:Histone acetyltransferases (HATs) GCN5/PCAF and CBP/p300 are transcription coactivators. However, how these HATs regulate ligand-induced nuclear receptor target gene expression remains unclear. Here we show in mouse embryonic fibroblasts (MEFs), deletion of GCN5/PCAF specifically eliminates acetylation on H3K9 (H3K9Ac) while deletion of CBP/p300 selectively reduces acetylation on H3K18 and H3K27 (H3K18/27Ac). Treating MEFs with a specific ligand for nuclear receptor PPARdelta induces sequential increases of H3K18/27Ac and H3K9Ac on the promoter of PPARdelta target gene Angptl4, which correlates with a robust ligand-induced Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9Ac but not H3K18/27Ac on Angptl4 promoter. Finally, we show CBP/p300 and their HAT activities are required, while GCN5/PCAF and H3K9Ac are dispensable, for ligand-induced PPARdelta target gene expression in MEFs. These results highlight the substrate and site specificities of HATs in cells, and suggest that GCN5/PCAF- and CBP/p300-mediated histone acetylations play distinct roles in regulating ligand-induced nuclear receptor target gene expression. PCAF and GCN5 have some redundant function. To identify PCAF/GCN5-regulated genes, immortalized MEFs with PCAF knockout and GCN5 conditional knockout were infected with retroviruses expressing either Cre recombinase or vector alone. We prepared duplicated RNAs from either vector or Cre infected cells (PCAF-/-;GCN5+/- or PCAF-/-;GCN5+/-) and RNAs from either Vector or Cre infected the other independently immortalized cells for 6 affymetrix microarray.

2013-12-31 | E-GEOD-20008 | biostudies-arrayexpress

The histone acetyltransferase HBO1 (KAT7) promotes efficient tip cell sprouting during angiogenesis

Project description:Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling.Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA-sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1 deleted retinas, which lead to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions suggesting that the role of HBO1 is as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis.

2021-09-30 | GSE161310 | GEO

The histone acetyltransferase HBO1 (KAT7) promotes efficient tip cell sprouting during angiogenesis

2021-09-30 | GSE161236 | GEO

PCAF/GCN5-regulated genes in MEFs

2013-12-31 | GSE20008 | GEO

Epigenomic profiling of EHMT1/2 depletion in PARPi-resistant HGSOC

Project description:Epigenomic profiling of EHMT1/2 depletion in PARPi-resistant HGSOC

| PRJNA929504 | ENA

Single cell RNA sequence reveals C5aR1 inhibition selectively targets pro-tumorigenic M2 macrophages reversing PARP inhibitor resistance

Project description:Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient thus requiring the development of combination therapies that can capitalize on PARPi activity. We thus explored mechanisms underlying sensitivity and resistance to PARPi using two intrinsically sensitive and resistant syngeneic murine breast cancer models. Our data indicate that the PARPi sensitive tumor model has a high ratio of M1 anti-tumor/M2 pro-tumor macrophages with the M1/M2 ratio being increased by PARPi. In contrast the PARPi resistant tumor model had very low levels of M1 macrophages and thus a low M1/M2 ratio that was not altered by PARPi. Our data indicate that co-transplantation of the PARPi sensitive and the PARPi resistant tumor results in accumulation of M2 macrophages in the sensitive tumor, rendering the sensitive tumor PARPi resistant. C5aR1 and RPS19/C5aR1 signaling is selectively elevated in the M2 macrophages that are associated with PARPi resistance. Strikingly C5aR1 targeting decreased M2 macrophages, while sparing M1 macrophages rendering PARPi resistant tumors sensitive to PARPi. Consistent with the murine data, human breast cancers with high C5aR1 levels have a poor response to immune checkpoint blockade. Thus targeting C5aR1 may represent a therapeutic approach to selectively deplete M2 macropahges and engender sensitivity to PARPi and potentially other therapeutic approaches.

2023-06-30 | GSE215908 | GEO

Transcriptome Analysis of Gene Expression involving C/EBPβ and Olaparib Resistance

Project description:Poly(ADP-ribose) polymerase inhibitors (PARPi) are now widely used in treating ovarian cancer. However, PARPi resistance emerges gradually. To investigate the change of gene expression during the transition, we have induced a stable resistant cell strain by culturing A2780 in the continued presence of olaparib. We then performed RNA-seq of the resistant strain and its parent line A2780. We found that C/EBPβ was strongly correlated with PARPi resistance. RNA-seq of C13* after C/EBPβ knockdown was also performed.

2021-05-15 | GSE153867 | GEO

The histone lysine acetyltransferase HBO1 regulates hematopoietic stem cell quiescence and self-renewal

Project description:KAT7 (HBO1) is a histone acetyltransferase required for histone H3 lysine 14 acetylation (H3K14ac) and normal levels of gene expression in hematopoietic stem and progenitor cells (HSPCs). The loss of H3K14ac was detected by western blot in whole bone marrow and by flow cytometry in specific HSPC populations. In order to determine the normal distribution of H3K14ac in the HSPC population a CUT&Tag experiment was performed using lineage negative, cKit positive Sca1 positive cells (LSK) and lineage negative, cKit positive Sca1 negative cells (progenitor cells). HBO1 was deleted using the poly(I:C) inducible MX1-cre recombinase transgene and compared to Kat7 heterozygous control cells, in which the MX1-cre was likewise induced. Analysis was performed at a stage when H3K14ac was no longer detectable by western blot. In order to control for the effects of PCR amplification and normalisation of library size before sequencing, equal numbers of Drosophila Schneider 2 cells were added to each sorted mouse cell population (“spike in”). After sequencing-read quality control, reads were mapped to a combined Mus musculus (Mm10) and Drosophila melanogaster (DmelR635) genome. To each mouse sample a normalisation factor based on the recovery of Drosophila reads within the same sample was applied. Genomic distribution of KAT7 (HBO1) was determined in control progenitor cells by CUT&Tag.

2021-10-13 | GSE185820 | GEO

RNA sequencing (RNA-SEQ) of RECQL4 knockdown by siRNA in ovarian cancer cells

Project description:The high frequency of somatic copy number alterations, as opposed to point mutations, is considered a unique feature of high-grade serous ovarian carcinoma (HGSOC). Amplification-dependent overexpression of RECQL4, which participates in DNA replication and repair, mediates the development of various cancers, but its pathobiological and clinical roles are poorly understood. Here, using bioinformatics analysis, RECQL4 amplification was found to occur in 27% of HGSOC samples in the TCGA cohort. RECQL4 was found to be upregulated and associated with a poor prognosis based on the immunohistochemistry staining of HGSOC. Functionally, RECQL4 overexpression increased proliferation and invasion of ovarian cancer cells both in vitro and in vivo. RECQL4 silencing had the opposite effects. In addition, RECQL4 knockdown enhanced the sensitivity of ovarian cancer cells to cisplatin and PARP inhibitor (PARPi). Further mechanistic investigations revealed that MAFB was a downstream target of RECQL4. The oncogenic effect of RECQL4 was attenuated after MAFB knockdown. Moreover, RECQL4 overexpression was negatively regulated by the tumour suppressor miR-10a-5p. Collectively, these findings indicate that genomic amplification and low expression of miR-10a-5p contribute to RECQL4 overexpression in ovarian cancer. This is the first study to reveal the oncogenic functions and clinical significance of RECQL4 in ovarian cancer.

2020-10-13 | GSE153839 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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