TAZ is involved in breast cancer cell migration via regulating actin dynamics
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ABSTRACT:
PROVIDER: PRJNA1103129 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28764400_1.fastq.gz | Fastqsanger.gz | |||
| SRR28764400_2.fastq.gz | Fastqsanger.gz | |||
| SRR28764401_1.fastq.gz | Fastqsanger.gz | |||
| SRR28764401_2.fastq.gz | Fastqsanger.gz | |||
| SRR28764396_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Cancer metastasis is dependent on cell migration. Several mechanisms, including epithelial-to-mesenchymal transition (EMT) and actin fiber formation, could be involved in cancer cell migration. As a downstream effector of the Hippo signaling pathway, transcriptional coactivator with PDZbinding motif (TAZ) is recognized as a key mediator of the metastatic ability of breast cancer cells. We aimed to examine whether TAZ affects the migration of breast cancer cells through the regulation of EMT or actin cytoskeleton. Methods: MCF-7 and MDA-MB-231 cells were treated with siRNA to attenuate TAZ abundance. Transwell migration assay and scratch wound healing assay were performed to study the effects of TAZ knockdown on cancer cell migration. Fluorescence microscopy was conducted to examine the vinculin and phalloidin. Semiquantitative immunoblotting and quantitative real-time PCR were performed to study the expression of small GTPases and kinases. Changes in the expression of genes associated with cell migration were examined through next-generation sequencing. Results: TAZ-siRNA treatment reduced TAZ abundance in MCF-7 and MDA-MB- 231 breast cancer cells, which was associated with a significant decrease in cell migration. TAZ knockdown increased the expression of fibronectin, but it did not exhibit the typical pattern of EMT progression. TGF-b treatment in MDA-MB-231 cells resulted in a reduction in TAZ and an increase in fibronectin levels. However, it paradoxically promoted cell migration, suggesting that EMT is unlikely to be involved in the decreased migration of breast cancer cells in response to TAZ suppression. RhoA, a small Rho GTPase protein, was significantly reduced in response to TAZ knockdown. This caused a decrease in the expression of the Rho-dependent downstream pathway, i.e., LIM kinase 1 (LIMK1), phosphorylated LIMK1/2, and phosphorylated cofilin, leading to actin depolymerization. Furthermore, myosin light chain kinase (MLCK) and phosphorylated MLC2 were significantly decreased in MDA-MB-231 cells with TAZ knockdown, inhibiting the assembly of stress fibers and focal adhesions. Conclusion: TAZ knockdown inhibits the migration of breast cancer cells by regulating the intracellular actin cytoskeletal organization. This is achieved, in part, by reducing the abundance of RhoA and Rho-dependent downstream kinase proteins, which results in actin depolymerization and the disassembly of stress fibers and focal adhesions.
2024-04-27 | GSE264547 | GEO
Project description:Here we show that enhancing polymerization of branched actin at the cell cortex by removing as many as 3 negative regulators promotes single cell migration, but not collective migration of mammary epithelial cells
2023-10-14 | GSE244924 | 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:YAP and TAZ are transcriptional co-activators that are often constitutively active in triple negative breast cancer (TNBC) cells. But the mechanisms responsible for YAP/TAZ dysregulation in TNBC remain unclear. We hypothesized that RhoGEF activity in TNBC cells underpins YAP/TAZ activation in TNBC cells. Through systematic RNAi screening we found that the Focal Adhesion (FA) associated RhoGEF DOCK5 promotes YAP/TAZ nuclear translocation in proliferating TNBC cells. DOCK5 is required for 2D migration and 3D invasion, acting as a coincident detector that maintains cell polarity by stabilising GSK3 activation downstream of CDC42 at polarized leading edges only where FAs are being assembled. DOCK5 and CDC42 are required for cell survival and drug resistance in TNBC cells. Based on these studies we propose that cancer cell phenotypes such as drug resistance can be driven by cells adopting polarised, migratory shapes.
2025-04-14 | PXD020102 | Pride
Project description:The Hippo pathway plays important roles in organ development, tissue homeostasis, and tumor growth, and its downstream effector TAZ is a transcriptional coactivator that promotes target gene expression through the formation of biomolecular condensates. However, the mechanisms that regulate the biophysical properties of TAZ condensates to enable Hippo signaling are not well understood. Here, using chemical cross-linking combined with an unbiased proteomic approach, we show that FUS associates with TAZ condensates and exerts a chaperone-like effect to maintain their proper liquidity and robust- transcriptional activity. Mechanistically, the low complexity sequence domain of FUS targets the coiled-coil domain of TAZ in a phosphorylation-regulated manner, which ensures the liquidity and dynamicity of TAZ condensates. In cells lacking FUS, TAZ condensates transition into gel/solid-like assembles with immobilized TAZ, leading to reduced expression of target genes and inhibition of pro-tumorigenic activity. Thus, our findings identify a chaperone-like function of FUS in Hippo regulation and demonstrate that appropriate biophysical properties of transcriptional condensates are essential for gene activation.
2023-02-17 | PXD040257 |
Project description:Cell function depends on the mechanical properties of the microenvironment. Cells probe these features by applying and transmitting forces to their surroundings, via their actomyosin cytoskeleton and adhesion complexes, and then transducing them into biochemical signals. Among these, the transcriptional coactivators YAP/TAZ recently emerged as key factors mediating some biological responses to actomyosin contractility in vitro. However, whether mechanical cues regulate YAP/TAZ activity in vivo, and whether this is relevant for adult tissue homeostasis, remains poorly understood. Here we show that the F-actin capping protein CAPZ is a critical regulator of actomyosin contractility, as its inactivation alters stress fiber and focal adhesion dynamics, leading to enhanced myosin activity and increased cellular traction forces. In vitro, this rescues YAP from inhibition by a small geometry; in vivo, inactivation of Capzb in the mouse liver induces YAP activation and hepatocyte proliferation, leading to striking organ overgrowth. Moreover, Capzb is essential for the maintenance of the differentiated hepatocyte state, and for the metabolic zonation of hepatocytes. In keeping with changes in tissue mechanics and activation of YAP, inhibition of ROCK or deletion of Yap1 reverse the phenotypes emerging in Capzb-null livers. These results indicate a previously unrecognized role for CAPZ in tuning the sensitivity of cells and tissues to mechanical signals, and a physiological function for F-actin dynamics in regulating organ growth and tissue homeostasis.
2019-03-19 | GSE116993 | GEO
Project description:Immune cells navigate through complex tissue architectures by extensive cellular deformation, low adhesion, and high cell velocities. Loss-of-function mutations in dedicator of cytokinesis 8 (Dock8) are associated with immunodeficiency as immune cells becoming entangled during migration through dense environments, but their migration on two-dimensional surfaces remains entirely intact. Here, we investigated the specific cytoskeletal defect of Dock8-deficient activated T cells and describe a central pool of F-actin in wild-type murine and human T cells that is absent in Dock8 knockout T cells. The appearance of the central actin pool is mechanoresponsive and emerges only when cells are very confined. We identified mammalian sterile 20-like (Mst1) as a necessary component in this mechanosensitive pathway in addition to Dock8, allowing for cell shape integrity and survival during migration through complex environments. Our work shows that loss of the central actin pool results in greater nuclear deformation, accrual of DNA damage, and premature cell senescence.
2025-10-08 | GSE272197 | GEO
Project description:Mutations mimicking growth factor-induced proliferation and motility characterize some aggressive subtypes of mammary tumors. To unravel novel players, we applied phosphoproteomics on untransformed mammary cells, which were pre-stimulated with the epidermal growth factor (EGF). This analysis identified ladinin-1 (LAD1), a hitherto poorly characterized protein, as a phosphor-effector of the EGF-to-ERK pathway. We report that LAD1 is essential for mammary cell proliferation and migration. LAD1 is transcriptionally induced, undergoes phosphorylation by EGF and co-localizes with actin stress fibers. Yeast 2-hybrids and co-immunoprecipitation screens revealed that LAD1 binds with filamins, actin cross-linking proteins. Co-sedimentation analyses attribute to LAD1 a role in actin treadmilling, probably in conjuction with SFN/14-3-3sigma. Depletion of LAD1 led to a decrease in viability related transcripts, and inhibited growth of mammary xenografts in an animal model. Furthermore, LAD1 is highly expressed in two aggressive subtypes of breast cancer, as well as predicts poor patient prognosis. These studies identify a new cytoskeletal component essential for signal transduction and for the acquisition of oncogenic attributes by human mammary tumors.
2018-01-31 | GSE103531 | GEO
Project description:Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of Sertoli cell actin cytoskeleton is vital for spermatogenesis but the underlying mechanism remains largely unclear. Here we report that RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Of particular, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics is controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins and PTBP1 is a key player in generating such isoforms.
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Project description:Inactivating Negative Regulators of Cortical Branched Actin Enhances Persistence of Single Cell Migration.
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