Browse
Submit Data
Databases
API
Help

Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PolyA-enriched RNA-seq of primary human hepatocyte spheroids treated with small molecule inhibitors targeting TEAD

ABSTRACT: TEAD1 emerged as an estrogen-sensitive gene that was upregulated in a HFD mouse model and in NAFLD patients. We investigated the roles of TEAD in NAFLD by treating primary human hepatocyte spheroids with two small molecule inhibitors blocking the TEAD/YAP interaction. One small molecule blocks the interaction by inhibiting TEAD autopalmitoylation (TEADap), the second small molecule blocks the interaction by binding to the surface of the TEAD protein (TEADsf).

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER:

PROVIDER: E-MTAB-13207 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): E-MTAB-11833

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

TEAD1 ChIP-seq on on MDA-MB-231 and Detroit X1 562 cells

Project description:The Hippo Pathway is a critical signaling network that regulates organ size and cellular proliferation in metazoans. The transcriptional enhanced associate domain (TEAD) family of transcription factors serve as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate expression of multiple genes involved in proliferation, cell-fate determination, polarity, and survival1. Recent work revealed that TEAD proteins are palmitoylated at a conserved cysteine with the lipid tail extending into the hydrophobic core of the protein2. Mutagenic and covalent modulation of the palmitoylation site disrupts Hippo signaling2,3; however, an understanding of why TEAD proteins require this seemingly essential modification and the therapeutic implications of modulating TEAD palmitoylation has remained elusive. Here we report the identification and optimization of a potent pan-TEAD small molecule that binds the TEAD lipid pocket (LP), blocks palmitoylation, and dysregulates TEAD activity in multiple cancer cell lines. Cellular and biochemical data interrogating the mechanism of action for our compound reveal TEAD palmitoylation to function as a checkpoint that regulates TEAD homeostasis. We show that bypassing this checkpoint with a small molecule increases TEAD protein levels thereby decreasing the ability of YAP/TAZ to activate downstream target gene transcription in a dominant-negative manner. Our study demonstrates a new role for lipidation in protein signaling and establishes the TEAD LP as a bona fide therapeutic site for modulation of the Hippo Pathway.

2020-06-03 | GSE139951 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor MGH-CP1 in Breast Cancer Cell Line

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in cancer cell line treated with TEAD palmitoylation inhibitor MGH-CP1, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods:Breast cancer cell line MDA-MB-231 was chosen to be treated with TEAD palmitoylation inhibitor MGH-CP1 at 10μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Results: MGH-CP1 specifically blocks TEAD transcriptional activity compared with YAP/TAZ siRNA in MDA-MB-231 cells. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor MGH-CP1 as specific small molecule to block TEAD transcriptional activity. We report the application of next generation sequencing technology for high-throughput profiling of TEAD palmitoylation inhibitor MGH-CP1 in breast cancer cells.

2021-05-11 | GSE140396 | GEO

Multicellular spheroids treated with the compound VLX600

Project description:Microarray based mRNA profiling was used to charactarize the response to the compound VLX600 in cells grown as spheroids. Cells used was colon cancer cells HCT116 and HCT116HIF1a knock-out. We identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to a bioenergetic catastrophe and tumor cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Microarray based mRNA profiling was used to charactarize the response to the compound VLX600 in cells grown as spheroids. Cells used was colon cancer cells HCT116 and HCT116HIF1a knock-out cells.

2014-02-17 | E-GEOD-53777 | biostudies-arrayexpress

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Project description:The Hippo pathway is a key growth-control pathway conserved across species. The downstream effectors of the Hippo pathway YAP/TAZ are frequently activated in cancer cells by a diverse array of mechanisms to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs are central to their transcriptional activities, we discovered a potent small molecule inhibitor (SMI) GNE-7883 that allosterically blocks the interactions between YAP/TAZ and all four TEAD paralogs in human cells through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models, and achieved strong anti-tumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes resistance to the recently approved KRAS G12C inhibitor sotorasib in both treatment-refractory and acquired resistance cell line models, providing strong proof-of-concept of TEAD SMIs in targeting YAP/TAZ-mediated KRAS inhibitor resistance. Taken together, this work demonstrates activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

2023-04-26 | GSE229071 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor MGH-CP1 in MDA-MB-231 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration inMDA-MB-231cells treated with TEAD autopalmitoylation inhibitor MGH-CP1, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods:Breast cancer cell line MDA-MB-231 was chosen to be treated with TEAD palmitoylation inhibitor MGH-CP1 at 10μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor MGH-CP1 as specific small molecule to block TEAD transcriptional activity.

2022-09-11 | GSE177052 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor TM2 in NCI-H226 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with new TEAD autopalmitoylation inhibitor TM2, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD palmitoylation inhibitor TM2 at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor TM2 as specific small molecule to block TEAD transcriptional activity in mesothelioma cells.

2024-05-01 | GSE203421 | GEO

RNA-Seq of liver from CLA-exposed mice with/without PPARα antagonist

Project description:We demonstrate that conjugated linoleic acid (CLA), when given to mice as a dietary supplement, induced an enlarged liver and hepatic steatosis. The progression of NAFLD and insulin resistance was reversed by GW6471 a small-molecule antagonist of PPARα. Transcriptional profiling of livers unraveled that genes involved in lipid metabolism core gene programs controlled by PPARα in response to CLA and GW6471.Our findings reveal a novel role of PPARα in the regulation of lipid homeostasis and highlight its druggable nature in NAFLD.

2021-08-27 | GSE159219 | GEO

Pupylation sites on protein EthR

Project description:We used the well-studied interaction between the secondary messenger molecule 3',5'-cyclic diguanosine monophosphate (c-di-GMP) and its receptor EthR to validate the efficiency of spider capturing protein and small molecule interaction and investigated the puoylation sites of EthR by mass spectrometry

2021-06-04 | PXD026522 | iProX

Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning

Project description:Background & Aims Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the disease so far. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here the aim is to investigate the effect of PKLR in in vivo model and reposition a drug which could be used for treatment of NAFLD. Results The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drugs were identified as potential inhibitor of PKLR by the drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues. Conclusion: In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which could be validated in further clinical trials.

2022-07-22 | GSE193627 | GEO

Targeting LIPA Independent of its Lipase Activity is a Therapeutic Strategy in Solid Tumors via Induction of Endoplasmic Reticulum Stress

Project description:Triple negative breast cancers (TNBC) are associated with poor clinical outcomes due to a lack of targeted therapies. Here, we identified a small molecule ERX-41 with potent activity against TNBC cell lines, primary tumor explants and xenografts. ERX-41 induced endoplasmic reticulum (ER) stress and caused cell death. We identified lysosomal acid lipase A (LIPA) gene as the molecular target for ERX-41 and critical for ERX-41 to induce ER stress and cell death. Mechanistically, interaction of ERX-41 with LIPA alters expression of multiple ER-resident proteins involved in protein folding. Importantly, we defined that ER localization of LIPA but not its lipase function are necessary for ERX-41 activity in TNBC. Our study implicates a new targeted strategy for multiple solid tumors, including breast, brain, pancreatic and ovarian, whereby a small orally bioavailable molecule (ERX-41) targeting LIPA blocks protein folding, induces ER stress and causes cell death.

2022-03-21 | MSV000089091 | MassIVE

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