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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE177052 | GEO | 2022/09/11

REPOSITORIES: GEO

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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

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

Next Generation Sequencing Quantitative Analysis of TEAD Inhibitors 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 TEAD inhibitors. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD inhibitors 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 TEAD inhibitors to block TEAD transcriptional activity in mesothelioma cells.

2022-10-15 | GSE215114 | GEO

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

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

| PRJNA589597 | ENA

Raw RNA-seq data of MEF cells treated with MGH-CP1

Project description:Raw RNA-seq data of MEF cells treated with control vehicles (DMSO) and MGH-CP1 (1uM in DMSO)for 2 and 4 days

2022-12-01 | GSE141494 | GEO

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

Lysine long-chain fatty acylation regulates the TEAD transcription factor

Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.

2023-03-19 | PXD033939 | Pride

Human malignant mesothelioma NCI-H226 cells treated with TEAD inhibitor K-975 in SCID mice.

Project description:We investigate the dependence of human malignant mesothelioma on functional TEAD transcription factors to maintain fully established tumors in vivo. We show that TEAD inhibitor K-975 stops tumor growth in vivo, eventually causing tumor regression, by downregulating TEAD activity and altering, thus, TEAD-dependent transcription in a dysfunctional Hippo genetic background. Our data validate the concept of inhibiting an activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196726 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [SubQ]

Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.

2023-10-04 | GSE222962 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [Invitro]

2023-10-04 | GSE222960 | GEO

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