YAP1/TAZ knockdown in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1081396 | ENA |
REPOSITORIES: ENA
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Project description:Targeted therapies in cancer are limited by cells exhibiting drug tolerance. We aimed to target drug tolerance in order to delay the development of acquired resistance. In melanoma, tolerance to MAPK pathway inhibitors is associated with loss of SOX10 and an enhanced TEAD transcriptional program. We show that loss of SOX10 is sufficient to up-regulate TEAD targets with dependence on the co-activator, TAZ. Active TAZ was sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. We developed novel covalent inhibitors, OPN-9643 and OPN-9652, designed to target the central palmitate binding pocket of TEADs. In SOX10-deficient cells, OPN-9643 and OPN-9652 reduced TEAD-dependent reporter activity and expression of TEAD targets, CTGF and CYR61. OPN-9643 and OPN-9652 treatment enhanced the inhibitory effects of MAPK-targeted therapies in 2D and 3D growth assays and reversed tolerance mediated by active TAZ. In vivo, OPN-9652 delayed the onset of acquired resistance to BRAF inhibitors and MEK inhibitors from minimal residual disease. Thus, TAZ-TEAD activity plays an important role in melanoma drug tolerance and the development of acquired resistance.
2025-07-22 | GSE259388 | GEO
Project description:YAP1 and TAZ knockdown in human keratinocytes
| PRJNA565787 | ENA
Project description:RNA sequencing (RNAseq) of N/TERT2G keratinocytes transduced with pooled siRNAs targeting YAP1 and TAZ (WWTR1), or non-targeting control siRNA (siCon)
2020-02-24 | GSE137531 | GEO
Project description:Promoting rumen development is closely related to the health and efficient growth of ruminants. In the present study, we aimed to assess the impact of YAP1/TAZ on RE proliferation. The transcriptomic expression was analyzed to investigate the potential regulatory networks. The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered in cells following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation through GA, the CCN1/2 increased to promote RE cell proliferation. While when the YAP1/TAZ was inhibited by VP, the BIRC3 decreased to suppress RE cell proliferation. Thus, YAP1/TAZ may be potential targets for regulating RE cell proliferation. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE and offer a potential target for promoting rumen development.
2024-04-03 | GSE252747 | GEO
Project description:The Hippo signaling pathway is evolutionarily well conserved, and all core components have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador), LATS1/2 (Warts), MOB1 (Mats), YAP1/TAZ (Yorkie), and TEAD1/2/3/4 (Scalloped) (Halder and Johnson, 2011; Pan, 2007; Dong et al., 2007; Saucedo and Edgar, 2007). When Hippo signaling is active, YAP1/TAZ is phosphorylated by LATS1/2 and sequestered by 14-3-3 proteins in cytoplasm. When Hippo signaling is absent, unphosphorylated YAP1/TAZ enters the nucleus and increases transcriptional activation of genes involved in cell proliferation and survival. The indispensability of the Hippo pathway in restricting cell growth and proliferation has prompted speculation that many members of the pathway might be involved in tumorigenesis. To see the effect of YAP1 and TAZ in HCC cell, we generated gene expression profile.
2014-12-31 | GSE54617 | GEO
Project description:The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ overcomes PLX4032 resistance, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and cytoskeletal tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a promising synthetic lethal strategy to suppress resistance in BRAF inhibitor therapies.
2015-11-18 | GSE68599 | GEO
Project description:We developed a mouse model of bile duct paucity by deleting Yes-associated protein 1 (YAP1) in foregut endoderm progenitors, using the Foxa3 promoter to drive Cre expression. YAP1 KO mice are viable postnatally and survive long-term despite a complete failure of intrahepatic bile duct development, resembling the liver phenotype of Alagille syndrome. Adult YAP1 KO mice suffer from severe chronic cholestasis, but show minimal hepatocellular injury, suggesting that the hepatocytes have adapted to preserve liver function and reduce damage from the toxicity of bile acids and bilirubin. We next bred Foxa3-Cre YAP1 KO TAZ heterozygote and Foxa3-Cre YAP1 KO TAZ KO (DKO) mice to assess the role of TAZ in this model. DKO mice and male YAP KO TAZ heterozygotes died around time of birth. The survivors, YAP1 KO TAZ heterozygote females, were overall phenotypically similar to YAP1 KO mice, with absence of intrahepatic bile ducts and long-term survival. We used RNA-seq to analyze the gene expression patterns of whole liver tissue of female adult YAP1 KO mice compared to WT controls (C57BL/6 background), and female adult YAP1 KO TAZ heterozygote (YKTH) mice compared to WT controls (mixed C57BL/6 - FVB background). We found that both YAP1 KO and YAP1 KO TAZ heterozygote female mice were overall very similar and showed similar alterations in gene expression compared to WT. There were a few differences in pathways involved in cell cycling and monocyte recruitment.
2023-07-20 | GSE213815 | GEO
Project description:Cancer cells with homologous recombination defects are particularly susceptible to PARP inhibitors (PARPi) and experience synthetic lethality. We found that the development of PARPi resistance in these cancer cells is associated with the formation of nuclear membrane-less condensates containing a specific YAP1 variant termed YAP1-2α, TAZ, TEAD, and BRD4. These nuclear condensates are generated through liquid-liquid phase separation (LLPS), initiated by the heterodimerization of YAP1-2α with TAZ, followed by multivalent interactions with mediator proteins to activate a super-enhancer. This super-enhancer facilitates the robustness of cancer cells by increasing cancer stemness, contributing to anti-cancer drug resistance not limited to PARPi. Our study underscores the unexpected connection between RNA splicing and the malignant grade of cancer. Targeting YAP1-2α/TAZ/TEAD-driven super-enhancers is a promising approach for overcoming resistance to cancer treatment.
2025-01-28 | GSE287274 | GEO
Project description:YAP1 (Yes-associated protein 1) and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1) are nucleo-cytoplasmic shuttling proteins that can function in the nucleus as transcriptional coactivators. Here we sought to evaluate which genes are regulated by endogenous levels of YAP/TAZ. We compared SK-N-MC cells transfected with a control non-targeting siRNA with cells transfected with a mix of siRNA targeting both YAP and TAZ.
2018-09-27 | GSE120512 | GEO
Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.
2020-05-26 | PXD018131 | Pride