Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1057080 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27346600_1.fastq.gz | Fastqsanger.gz | |||
| SRR27346600_2.fastq.gz | Fastqsanger.gz | |||
| SRR27346601_1.fastq.gz | Fastqsanger.gz | |||
| SRR27346601_2.fastq.gz | Fastqsanger.gz | |||
| SRR27346602_1.fastq.gz | Fastqsanger.gz |
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Project description:Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of BLCA cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (FDPS knockdown, simvastatin or zoledronic acid) significantly reduced the migratory ability of BLCA cells. Therefore, we tested the changes of key genes after knocking down the key enzymes of the mevalonate pathway, FDPS and SQLE1, and the transcription factor YY1 in bladder cancer cells using RNA sequencing.
2024-09-08 | GSE252007 | GEO
Project description:The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy.
| S-EPMC11550803 | biostudies-literature
Project description:Cell states are governed by cell-intrinsic properties and external cues that regulate cell shape and signaling via cell-cell junctions or adhesions. Integrin β1-mediated adhesion is dispensable in early mouse embryogenesis at pre-implantation but becomes indispensable post-implantation. This implies distinct roles for β1-integrins in the naïve pre-implantation and primed post-implantation pluripotent stem cells (PSC). These, however, remain poorly understood. We investigated β1-integrin control of naïve-like and primed human induced PSC (hiPSC). We find that integrin β1 is active in naïve and primed hiPSCs and the degree of activity varies in vitro on different ECMs. Inhibition of integrin β1 in primed hiPSCs induces naïve-like colony features, reduces actomyosin contraction and ERK activity and alters gene expression, indicative of more naïve-like features. Integrin β1 inhibition supports epigenetic reversion of primed PSC to a naïve-like status, which involves dramatic reorganization of colony morphology, actin and adhesions. Furthermore, continued β1 integrin inhibition facilitates the maintenance of a naïve-like state through gene expression. These data reveal unprecedented integrin-dependent regulation of PSC states and demonstrate how integrin inhibitors may help to fine-tune hiPSC function and properties in vitro.
2025-06-03 | GSE205423 | GEO
Project description:Cell states are governed by cell-intrinsic properties and external cues that regulate cell shape and signaling via cell-cell junctions or adhesions. Integrin β1-mediated adhesion is dispensable in early mouse embryogenesis at pre-implantation but becomes indispensable post-implantation. This implies distinct roles for β1-integrins in the naïve pre-implantation and primed post-implantation pluripotent stem cells (PSC). These, however, remain poorly understood. We investigated integrin β1 control of naïve-like and primed human induced PSC (hiPSC) states. We find that integrin β1 is active in naïve and primed hiPSCs and the degree of activity varies in vitro on different extracellular matrices (ECMs). Integrin β1 inhibition in primed hiPSCs induces naïve-like colony features, reduces actomyosin contraction and ERK activity and alters gene expression, indicative of more naïve-like features. Reverting the primed state of pluripotency to naïve involves dramatic reorganization of colony morphology, actin and adhesions. Importantly, functional and single-cell transcriptomics analyses demonstrate that integrin β1 inhibition attenuates colony morphology transitions in cells exiting naïve pluripotency. These data reveal unprecedented integrin-dependent regulation of PSC states and demonstrate how integrin inhibitors may help to fine-tune hiPSC function and properties in vitro.
2025-05-19 | GSE282224 | GEO
Project description:Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are comprised of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.
2025-07-08 | GSE301773 | GEO
Project description:GATA3 Promotes Ferroptosis Resistance by Repressing Integrin β1 Signaling
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Project description:Integrins provide an essential bridge between cancer cells and the extracellular matrix, playing a central role in every stage of disease progression. Despite the recognized significance of integrin phosphorylation in several biological processes, the regulatory mechanisms and their relevance remained elusive. To address this gap, we engineered a fluorescence resonance energy transfer biosensor for integrin β1 phosphorylation, screening 96 protein tyrosine phosphatases and identifying Shp2 and PTP-PEST as negative regulators. Mutation of the integrin NPxY(783/795) sites revealed the importance of integrin phosphorylation for efficient cancer cell invasion, further supported by inhibition of the identified integrin phosphorylation regulators Shp2 and Src kinase. Using proteomics approaches, we uncovered Cofilin as a component of the phosphorylated integrin-Dok1 complex and linked this axis to effective invadopodia formation, a process supporting breast cancer invasion. These data further implicate dynamic modulation of integrin β1 phosphorylation at NPxY sites at different stages of metastatic dissemination.
2025-02-05 | PXD048646 | Pride
Project description:β1-integrin is the major β-integrin subunit expressed in both lens epithelial and fiber cells. Our previous research indicated that β1-integrin is essential for the maintenance of lens epithelial integrity and survival in late embryonic lens development (Simirskii et al, 2009). Lack of β1-integrin in the lens will lead to severe micropthalmia and lack of lens in adult mice. In order to study the mechanisms involved, high throughput RNA sequencing (RNAseq) was performed to determine the genes that are differentially expressed between E15.5 wild type (WT) lenses and lenses that lack β1-integrin expression due to the action of MLR10 CRE (β1-cKO). The methodology used here is similar to the other RNAseq experiments that were previously performed in our lab (Manthey et al., 2014a and Audette et al, 2015) (Geo accession: GSE 49949 and GSE69940) . Meanwhile, the filtering criteria and processing procedures were also published (Manthey et al., 2014b). Compared to WT, 120 genes were found to be differentially expressed in β1-cKO lenses. Moreover, bioinformatics tools (DAVID (the database for Annotation, Visulization and Integrated Discovery), and PANTHER (Protein Analysis through Evolutionary Relationship) classification system) as well as manual literature searching was applied for further data analysis. It showed that genes involved in EMT and stress-responses were differentially expressed in β1-cKO compared to that of WT. Description of filtering criteria: To identify the differentially expressed genes, pair-wise qCML method exact tests with a Benjamini Hochberg false discovery rate correction greater than the threshold of P<0.05 was applied, which identified 5120 genes. As previously described (Manthey et al., 2014b), most of the genes differentially expressed between inbred C57Bl/6 <har> and mice with a mixed background were below a threshold of 2.5 fold change. Therefore, all differentially expressed genes with a less than 2.5 fold change were filtered out. Further, genes whose expression level were not high enough to be biologically significant were also filtered out, based on the RPMK (Reads per Kilobase per million reads) value. Any gene in the final list has RPKM greater that 2 in either WT or β1-cKO samples, a value that corresponds to approximately 1 mRNA molecule per cell. By applying a combination of these filtering criteria, 120 differentially expressed genes were found, which could potentially elucidate the molecular connections between conditional deletion of β1-intergrin from the lens and the observed phenotypic abnormalities. Manthey, A. L., Lachke, S. A., FitzGerald, P. G., Mason, R. W., Scheiblin, D. A., McDonald, J. H. and Duncan, M. K. (2014a) 'Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development', Mech Dev 131: 86-110. Manthey, A. L., Terrell, A. M., Lachke, S. A., Polson, S. W. and Duncan, M. K. (2014b) 'Development of novel filtering criteria to analyze RNA-sequencing data obtained from the murine ocular lens during embryogenesis', Genom Data 2: 369-374.
2017-08-31 | GSE77188 | GEO
Project description:Purpose: RhoB regulates cell functions, such as vesicular transport, apoptosis, autophagy, DNA repair, angiogenesis, proliferation, migration and invasion. We investigated whether RhoB is involved in the pathogenesis of ulcerative colitis (UC).We performed RNA sequencing analysis in intestinal epithelial cells (IECs) from RhoB-deficient mice and WT mice to study the molecular mechanisms through which RhoB regulates goblet cell numbers and epithelial regeneration and confirmed findings in colonic organoids from RhoB-deficient mice and WT mice and siRhoB transfected SW480 cells.
2022-09-27 | GSE170994 | GEO
Project description:Integrin β1 demarks precursors of brain-residing antibody-secreting cells in multiple sclerosis
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