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Expression profile of osteosarcoma cells in which Sox2 maintains cancer stem cells

ABSTRACT: Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes. The Hippo pathway has a profound tumor suppressive role in cancer by restraining the strong growth-promoting function of YAP. We have previously shown that the stem cell transcription factor Sox2 maintains the tumorigenicity of osteosarcoma cancer stem cells (CSCs). In this report, we describe that Sox2 maintains stemness by antagonizing the Hippo pathway via direct repression of Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), thereby leading to exaggerated YAP function. YAP is potently oncogenic in osteosarcoma and its depletion sharply reduces the tumorigenic CSC fraction. Low Nf2, low WWC1, and high YAP expression mark the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. This Sox2-Hippo axis is conserved and also operates in other Sox2-dependent cancers such as glioblastomas. We propose that disruption of YAP transcriptional activity reduces CSCs and could be a therapeutic strategy for Sox2- dependent tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE64965 | GEO | 2015/02/15

SECONDARY ACCESSION(S): PRJNA272604

REPOSITORIES: GEO

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Expression profile of osteosarcoma cells in which Sox2 maintains cancer stem cells

Project description:Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes. The Hippo pathway has a profound tumor suppressive role in cancer by restraining the strong growth-promoting function of YAP. We have previously shown that the stem cell transcription factor Sox2 maintains the tumorigenicity of osteosarcoma cancer stem cells (CSCs). In this report, we describe that Sox2 maintains stemness by antagonizing the Hippo pathway via direct repression of Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), thereby leading to exaggerated YAP function. YAP is potently oncogenic in osteosarcoma and its depletion sharply reduces the tumorigenic CSC fraction. Low Nf2, low WWC1, and high YAP expression mark the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. This Sox2-Hippo axis is conserved and also operates in other Sox2-dependent cancers such as glioblastomas. We propose that disruption of YAP transcriptional activity reduces CSCs and could be a therapeutic strategy for Sox2- dependent tumors. Gene expression of 482 mouse lines mOS482 were analyzed by microarray. 3 replicates each of scrambled and Sox2shRNA were processed and hybridized

2015-02-15 | E-GEOD-64965 | biostudies-arrayexpress

Transcriptional targets of Hippo signaling in mammalian cells

Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.

2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress

Gene expression changes caused by YAP overexpression and Nf2 deletion in the developing mouse brain

Project description:The transcriptional coactivator YAP is the key downstream effector of the Hippo pathway. YAP overexpression in the developing mouse brain results in excessive expansion of the neural progenitor pool and severe perturbation of brain development. Nf2/Merlin is a tumor suppressor whose mutations are found in many human cancers. Loss of Merlin during brain development causes overexpansion of the neural progenitor pool. We used microarrays to identify the gene expression changes caused by YAP overexpression and Nf2 deletion. We used a double-transgenic system to overexpress YAP in the developing mouse brain by crossing mice carrying a doxycycline-dependent allele of YAP1-S127A (TetO-YAP1) with those expressing the reverse tetracycline-dependent transactivator rtTA under the control of the neural progenitor-specific Nestin promoter (Nes-rtTA) and feeding the dam with doxycycline-containing food (200 mg/kg) from E7.5. We conditionally deleted Nf2 using the telencephalon-specific Emx1-Cre.

2013-06-19 | E-GEOD-48078 | biostudies-arrayexpress

Global microRNA expression analysis in HaCaT human keratinocytes transfected with p72 or control EGFP in addition to siRNAs for NF2 and LATS2.

Project description:Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here we show that YAP, the downstream target of the tumor-suppressive Hippo signaling pathway regulates miRNA biogenesis in a cell density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding post-transcriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer. Two conditions (transfection of p72 or control EGFP in addition to siRNAs for NF2 and LATS2) were analyzed in duplicate.

2014-03-03 | E-GEOD-52205 | biostudies-arrayexpress

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer

Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.

2024-07-25 | PXD044829 | Pride

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer (part2)

2024-07-25 | PXD054192 | Pride

Hippo pathway component WWC1 is a key regulator of apoptosis and photosensitivity in lupus keratinocytes

Project description:Skin inflammation and photosensitivity are common manifestations of cutaneous and systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Non-lesional SLE skin exhibits increased UVB-driven cell death that persists in culture, supporting a potential role for epigenetic modifications to sustain this phenotype. We thus examined differential DNA methylation of non-lesional SLE vs. healthy control keratinocytes (KC) and identified Hippo signaling as the top significantly differentially methylated pathway, likely driven by hypomethylation of WWC1, a scaffold protein and Hippo pathway regulator. Analysis of non-lesional SLE skin biopsies and SLE keratinocytes in culture confirmed WWC1 overexpression that led to enhanced phosphorylation of YAP resulting in a pro-apoptotic transcriptional profile reflective of decreased YAP/TEAD transcriptional coactivation. Functional studies of UV-mediated apoptosis confirmed a regulatory role for YAP/TEAD interactions, and blockade of overactive Hippo signaling via a LATS1/2 inhibitor abrogated enhanced apoptosis in SLE KCs. Thus, our work identifies a novel mechanistic paradigm in SLE KCs in which aberrant UVB-apoptosis is driven by Hippo signaling via promotion of YAP phosphorylation and restriction of YAP coactivation of TEAD transcriptional activity. Hippo modulation may be a novel target for photosensitivity in SLE and CLE.

2023-07-06 | GSE198972 | GEO

Crosstalk between the STAT3, NF-kB and Notch signaling pathways in glioblastoma stem cells

Project description:In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma. GBM6 cells were continuously maintained as subcutaneous xenografts in NSG mice, and monolayer and CSC cultures were derived from freshly harvested tumor tissue. A total of 6 samples were subjected to microarray analysis, with three biological replicates for each experimental condition.

2013-06-19 | E-GEOD-48079 | biostudies-arrayexpress

Gene expression changes caused by YAP overexpression and Nf2 deletion in the developing mouse brain

2013-06-19 | GSE48078 | GEO

Mefloquine disrupts cancer stem cells by inhibiting lysosomal RAB5/7 mediated mitophagy

Project description:BACKGROUND & AIMS Cancer stem cells (CSCs) establish hierarchy in tumor tissue and a critical role for acquisition of resistance to therapy. Thus, the targeting of CSCs is important. We focused on lysosome which characteristically upregulated in colon CSCs for the aim of CSC targeting and search for new maintenance of CSCs by analyzing the function of CSC targeting drug. METHODS Correlation of lysosomal activity and CSC markers was assessed and single sphere formation and limiting dilution assay were performed, to evaluate CSCs property. Additionally, in vitro and vivo, we evaluated that anticancer drugs, antimalarial drugs, antitumor effect by combining them, and changes in cancer stem cell hierarchy. We performed microarray analyses to compare gene expression patterns from the tumors of treated patient derived xenograft mice. RESULTS LC3B+ or Lysotracker+ cells were characteristically existed in CD44V9+/ CD133+ CSC fraction as a small cell subpopulation. Single sphere formation assay and limiting dilution assay showed higher sphere formation activity and higher tumorigenic activity of LC3B+ or Lysotracker+ cells compared to LC3B－or Lysotracker－cells. Mefloquine treatment significantly decreased CD44v9+/ CD133+ cell number than representative antimalarial drugs, chloroquine and hydroxychloroquine. Mefloquine demonstrated the synergic effect on oxaliplatin and irinotecan. In Microarray analysis, we elucidated that mefloquine disrupted lysosome pathway by inhibiting Rab5 and Rab7. In patient-derived colon cancer tissue xenografted (PDX) mouse model, combined treatment of mefloquine with oxaliplatin or irinotecan drastically abrogated the tumorigenic activity of cancer cells. CONCLUSIONS Lysosomal activity in CSCs is a promising therapeutic target, and repositioning of mefloquine to colon cancer together with conventional chemotherapeutic agent will be a promising strategy for cure of colon cancer.

2018-06-20 | GSE116023 | GEO

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