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Sox9 controls self-renewal of oncogene targeted cells and links tumor initiation and invasion [Affymetrix]

ABSTRACT: Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in human, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog (HH) signaling completely prevents BCC formation and leads to a progressive loss of oncogene expressing cells. Transcriptional profiling of oncogene expressing cells with Sox9 deletion, combined with in vivo ChIP-sequencing uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix (ECM) deposition and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that links tumor initiation and invasion.

ORGANISM(S): Mus musculus

PROVIDER: GSE68613 | GEO | 2015/05/13

SECONDARY ACCESSION(S): PRJNA283209

REPOSITORIES: GEO

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Sox9 controls self-renewal of oncogene targeted cells and links tumor initiation and invasion [ChIP-Seq]

Project description:Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in human, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog (HH) signaling completely prevents BCC formation and leads to a progressive loss of oncogene expressing cells. Transcriptional profiling of oncogene expressing cells with Sox9 deletion, combined with in vivo ChIP-sequencing uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix (ECM) deposition and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that links tumor initiation and invasion. Sox9 ChIP-seq analysis in K14CreER SmoM2 cells.

2015-05-13 | E-GEOD-68755 | biostudies-arrayexpress

Sox9 controls self-renewal of oncogene targeted cells and links tumor initiation and invasion [ChIP-Seq]

2015-05-13 | GSE68755 | GEO

Effect of lentiviral-based shRNA-mediated knockdown of ZFX on the human medulloblastoma (MB) cell-line DAOY

Project description:The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation, whereas its aberrant activation causes tumor formation. Hh-induced tumors can arise from different tissues and can be indolent or highly aggressive, such as basal cell carcinoma (BCC) of the skin and neural progenitor-derived medulloblastoma (MB), respectively. Little is known about cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of several stem cell types, whereas its role in malignant transformation remains controversial. We found that the deletion of Zfx prevented BCC formation and significantly delayed MB development caused by Hh activation in vivo. In contrast, Zfx was dispensable for the development of Hh-independent brain tumor glioblastoma. We used genome-wide expression and chromatin binding analysis in a human MB cell line to identify direct, evolutionarily conserved targets of Zfx. These targets included the Hh signal transducer Smoothened (Smo), suggesting that Zfx may directly control Hh pathway activation in tumors. Two additional targets of Zfx, Dis3L and Ube2j1, were also required for the growth of MB cells in vitro. These results identify a common cell-intrinsic regulator of diverse Hh-induced tumors, and suggest Zfx and Zfx-controlled genes as possible therapeutic targets in these malignancies.

2014-12-31 | GSE45265 | GEO

Anti-ZFX ChIP-seq in a human medulloblastoma cell line

2014-12-31 | GSE45394 | GEO

Novel Targets of the Transcription Factor Sox9 in Neonatal Mouse Limb

Project description:Sox9 is an SRY-related transcription factor required for expression of cartilaginous matrix genes in the developing skeletal system and heart valve structures. In contrast to positively regulating formation of cartilaginous matrix, Sox9 has also been shown to negatively regulate matrix mineralization associated with bone formation. While the transcriptional activation of Sox9 target genes during chondrogenesis has been well studied, the mechanisms by which Sox9 represses osteogenic processs are not so clear. To address this, we performed a genome-wide Sox9 ChIP-on-chip approach using neonatal mouse lim tissue. Chromatin immunoprecipitation was performed with pooled Sox9 antibodies and normal rabbit IgG as control using neonatal mouse limb tissue. Samples include Sox9 IP and IgG IP.

2011-11-01 | E-GEOD-29058 | biostudies-arrayexpress

SOX9 modulates the expression of key transcription factors required for heart valve development

Project description:Heart valve formation initiates when endothelial cells of the heart transform into mesenchyme and populate the cardiac cushions. The transcription factor, SOX9, is highly expressed in the cardiac cushion mesenchyme, and is essential for heart valve development. Loss of Sox9 in mouse cardiac cushion mesenchyme alters cell proliferation, embryonic survival, and disrupts valve formation. Despite this important role, little is known regarding how SOX9 regulates heart valve formation or its transcriptional targets. Therefore, we mapped putative SOX9 binding sites by ChIP-Seq in embryonic day (E) 12.5 heart valves, a stage at which the valve mesenchyme is actively proliferating and initiating differentiation. Embryonic heart valves have been shown to express a high number of genes that are associated with chondrogenesis, including several extracellular matrix proteins and transcription factors that regulate chondrogenesis. Consequently, we compared regions of putative SOX9 DNA-binding between E12.5 heart valves and E12.5 limb buds. We identified context-dependent and contextâindependent SOX9 interacting regions throughout the genome. Analysis of context-independent SOX9 binding suggests an extensive role for SOX9 across tissues in regulating proliferation-associated genes including key components of the AP-1 complex. Integrative analysis of tissue-specific SOX9 interacting regions and gene expression profiles on Sox9-deficient heart valves demonstrated that SOX9 controls the expression of several transcription factors with previously identified roles in heart valve development, including Twist1, Sox4, Mecom/Evi1 and Pitx2. Together, our data identifies SOX9 coordinated transcriptional hierarchies that control cell proliferation and differentiation during valve formation. Examination of SOX9 binding sites in E12.5 atrioventricular canal (AVC) and E12.5 embryonic limb and mRNA expression profiling in E12.5 WT and Sox9 mutant AVCs, in duplicate.

2015-11-05 | E-GEOD-73225 | biostudies-arrayexpress

Effect of Misexpression of Sox9 on Gastric Differentiation

Project description:To determine if Sox9 was sufficient to drive mucous differentiation in the gastric epithelium, we bred mice carrying alleles for ROSA26rtTA.IRES.EGFP, TetO-Sox9, and Fgf20Cre.GFP. In these mice, cells expressing Cre will induce rtTA from the ROSA26rtTA.IRES.EGFP allele. To explore transcriptional changes following adult misexpression of Sox9, we isolated RNA from the corpus of Fgf20Cre.GFP/Cre.GFP; ROSA26rtTA.IRES.EGFP/rtTA.IRES.EGFP; TetO-Sox9 pup (misexpression animals) and ROSA26rtTA.IRES.EGFP/rtTA.IRES.EGFP; TetO-Sox9 pup (control) animals and performed RNA-sequencing.

2023-08-30 | GSE230101 | GEO

Ectopic expression of Sox9 led to differential gene expression in HepG2 cells

Project description:We generated the HepG2 subline stably expressing Sox9 (HepG2-Sox9) and performed transcriptome RNA sequence.

2021-05-28 | GSE175627 | GEO

ECM composition dictates the mode of cell competition and competence for tumor initiation

Project description:The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. Basal cell carcinoma (BCC) is the most frequent cancer in human4,5. Cell competition, the elimination of less fit cells by their neighboring winners, has been proposed to be important for tumour initiation6-10. Recent studies identified somatic mutations in cancer drivers in normal tissues lead to clonal expansion of these mutated cells11-16. However, the ways in which oncogenic mutations impact the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development is currently unknown. Using multidisciplinary approaches which combine lineage tracing, clonal analysis in living animals, single cell sequencing, quantitative proteomics, and functional experiments, we have investigated the mode of cell competition and the ability of oncogene-expressing cells to develop invasive BCC in different skin regions. The quantitative proteomics analysis of the ear and backskin dermis before and 6 weeks after oncogene expression was performed to investigate whether a different composition of the dermis in the ear and the backskin affects the ability of oncogene targeted cells to form BCC. To investigate whether a different composition of the dermis in the ear and the backskin affects the ability of oncogene targeted cells to form BCC, we performed an unbiased quantitative proteomics analysis of the ear and backskin dermis before and 6 weeks after oncogene expression. This analysis revealed that only very few proteins were more highly expressed in the backskin as compared to the ear and included Col1a1 and Col1a2 in WT conditions.

2023-11-27 | PXD041644 | Pride

Novel Targets of the Transcription Factor Sox9 in Neonatal Mouse Limb

2011-11-01 | GSE29058 | GEO

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