YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis
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ABSTRACT:
PROVIDER: PRJNA753454 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15403056.fastq.gz | Fastqsanger.gz | |||
| SRR15403057.fastq.gz | Fastqsanger.gz | |||
| SRR15403058.fastq.gz | Fastqsanger.gz | |||
| SRR15403059.fastq.gz | Fastqsanger.gz | |||
| SRR15403060.fastq.gz | Fastqsanger.gz |
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Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovered a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.
2021-08-20 | GSE181771 | GEO
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| S-EPMC8649869 | biostudies-literature
Project description:Neural crest cells (NCCs) are multipotent stem cells with a remarkable ability to differentiate into multiple cell lineages, including osteoblasts and chondrocytes. NCCs contribute to the majority of craniofacial skeleton, yet the molecular mechanisms regulating NCCs diversification into osteoblasts or chondrocytes remain poorly understood. We found that Yap and Taz function redundantly as key determinants of the osteogenesis versus chondrogenesis fate decision and differentiation in NCCs in vitro, ex vivo and in vivo, and Yap/Taz-deficiency in NCCs resulted in a switch from osteogenesis to chondrogenesis. Comprehensive analysis of unbiased datasets including CUT&RUN-seq and RNA-seq indicated that Yap/Taz directly regulate key genes that govern osteogenesis and chondrogenesis. During NCC-derived osteogenesis, Yap/Taz promote expression of osteogenic genes such as Runx2 and Sp7 but repress expression of chondrogenic genes such as Sox9 and Col2a1. Further, we found Yap/Taz directly interact with β-catenin in NCCs to coordinately promote osteoblast differentiation and repress chondrogenesis. Together our data indicate that Yap/Taz promote osteogenesis in NCCs by preventing chondrogenesis, partly through interactions with the Wnt-β-catenin pathway.
2022-11-02 | GSE154332 | GEO
Project description:The optic vesicle comprises a pool of bi-potential progenitor cells from which the retinal pigment epithelium (RPE) and neural retina fates segregate during ocular morphogenesis. Several transcription factors and signaling pathways have been shown to be important for RPE maintenance and differentiation, but an understanding of the initial fate specification and determination of this ocular cell type is lacking. We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish. A Teadresponsive transgene is expressed within the domain of the optic cup from which RPE arises, and Yap immunoreactivity localizes to the nuclei of prospective RPE cells. yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma. Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE. The mechanism of Yap dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor. In contrast to loss of Yap and Taz, overexpression of either protein within optic vesicle progenitors leads to ectopic pigmentation in a dosagedependent manner. Overall, this study identifies Yap and Taz as key early regulators of RPE genesis and provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson’s chorioretinal atrophy and congenital retinal coloboma. 60 pooled eyes from 36 hpf wild type or vsx2:Gal4/dsRed:14xUAS:YapS87A embryos were pooled for one sample. Three wild type and three vsx2:Gal4/dsRed:14xUAS:YapS87A pools were analyzed for RNA.
2015-08-06 | E-GEOD-71681 | biostudies-arrayexpress
Project description:Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells to lose cellular identity and acquire squamous alveolar type 1 (AT1) fate in the lungs. Significantly, this cell fate conversion is mediated via distinctive transitional cell states of Damage-Associated Transient Progenitors (DATPs), recently known to emerge during injury repair, in mouse and human lungs. Further, YAP/TAZ signaling is identified to realign the amino acid metabolism by modulating mTORC1-ATF4 activity, which is integral to fate conversion of secretory cells into AT1 fate. We observed aberrant activation of the YAP/TAZ-mTORC1-ATF4 axis in the altered airway epithelium of human pulmonary fibrosis where the emergence of DATPs and A1 cells is prominent. Finally, genetic and pharmacologic inhibition of mTORC1 activity restores lineage alteration and subepithelial fibrosis driven by YAP/TAZ activation, proposing a potential therapeutic target for human fibrotic lung diseases.
2021-06-25 | GSE178829 | GEO
Project description:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.
2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress
Project description:The two effector proteins of the Hippo signaling pathway, YAP and TAZ, play a pivotal role in the cellular homeostasis of podocytes and in the pathogenesis of focal segmental glomerulosclerosis (FSGS). We aim to unravel the unique and redundant functions of YAP and TAZ in the podocyte by identifying podocyte-specific interactors. We generated stable heat sensitive mouse podocytes (hsMPs) carrying a single copy integration of a transgenic construct expressing a flagged version of mouse Yap (3XFLAG.YAP), Taz (3XFLAG.TAZ) or Ruby (3XFLAG.RUBY) in the Rosa26 locus. To explore the interactome of YAP and TAZ in podocytes we immunoprecipitated the tagged proteins and characterized the co-immunoprecipitated protein complexes by mass spectrometry. Within the interactome analyses of the hsMPs, we identified shared and non-shared interacting proteins between YAP and TAZ. Among these identified proteins many well established interactors of YAP and TAZ were included, like proteins of the Tead family, different angiomotins or large tumor suppressor kinase 1 (Lats1). Strikingly, among the shared proteins were numerous proteins of the nuclear shuttling machinery, like importins (Ipo), exportins (Xpo), transportins (Tnpo) and nucleoporins (Nup) that form the nuclear pore complex (NPC), such as NUP107, NUP133, NUP205 and XPO5.
2024-01-26 | PXD040448 | Pride
Project description:Transcriptome analysis of prostate cancer patient derived organoid DU145 cell line upon knockdown of YAP, TAZ, or YAP/TAZ mediated by siRNAs
2022-03-24 | GSE199347 | GEO
Project description:Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding of the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive pro-tumorigenic signals in OSCC. Regions of pre-malignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in pro-tumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (YAP/TAZ) in human SCC2 oral cancer cells. Human SCC2 oral cancer cells were transfected with control siRNA, or siRNAs targeting TAZ, YAP, or YAP/TAZ for 48 hours. Total RNA from three independent experiments carried out on separate days was isolated and purified and the samples were then profiled on Affymetrix Human Gene 2.0 Chips at the Boston University Microarray Core. The expression profiles were processed and normalized using the Robust Multi-array Average (RMA) procedure (23) based on a custom Brainarray CDF (24). For each of the siRNA experiments, signatures of genes differentially expressed between treatment and corresponding siRNA control with an FDR q-value ?0.05 and a fold change ?2 were identified as either activated (up-regulated in control) or repressed (up-regulated in treatment). The overlap between the differentially expressed gene signatures was evaluated by Fisher test. Hierarchical gene and sample clustering was performed on the top 3000 genes with highest median absolute deviation (MAD; a robust version of the variance) across 12 samples, using “ward” as the agglomeration rule, and 1 minus Pearson correlation and Euclidean as the distance measures for genes and samples, respectively.
2015-05-26 | E-GEOD-66949 | biostudies-arrayexpress