Project description:RNA sequencing (RNAseq) of N/TERT2G keratinocytes transduced with TEAD inhibitor protein (TEADi) or control GFP for 12, 24 and 48 hs
Project description:RNA sequencing (RNAseq) of primary keratinocytes from mouse basal cell carcinoma mice (BCC) transduced with pooled siRNAs targeting YAP1 and TAZ (siYT) or non-targeting control siRNA (siCon), and with TEADi or GFP as control
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.
Project description:The Hippo tumour suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some now entering clinical trials for different cancers. Here, we investigated the cellular response to TEAD palmitoylation inhibitors, using genomic and genetic strategies. Genome-wide CRISPR/Cas9 screens revealed that mutations in genes from the Hippo, MAPK and JAK-STAT signaling pathways all modulate the cellular response to TEAD inhibition. Inhibition of TEAD palmitoylation strongly reduced YAP/TEAD target expression, whilst only mildly impacting YAP/TEAD genome binding. Additionally, expression of MAPK pathway genes was induced upon inhibition of TEAD palmitoylation, which coincided with YAP/TEAD redistribution to AP-1 transcription factor binding sites. Consistent with this, combined inhibition of TEAD and the MAPK protein MEK, synergistically blocked proliferation of several mesothelioma and lung cancer cell lines and more potently reduced the growth of patient-derived lung cancers in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.
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.
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.
Project description: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).
