SOX9 overexpression in melanoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57463 | GEO | 2014/05/09
SECONDARY ACCESSION(S): PRJNA246497
REPOSITORIES: GEO
Similar Datasets
Project description:SOX9 is generally not expressed in melanomas with a high proliferative capacity but is expressed in melanomas with a high invasive capacity. Here we overexpress full length SOX9 in M010817, a melanoma cell culture with high proliferative capacity but low invasive capacity. 3x Control vector. 3x SOX9 overexpression
2014-05-09 | E-GEOD-57463 | biostudies-arrayexpress
Project description:Introduction: In addition to the well-known cartilage extracellular matrix-related expression of Sox9, we demonstrated that chondrogenic differentiation of progenitor cells is driven by a sharply defined bi-phasic expression of Sox9: an immediate early and a late (extracellular matrix associated) phase expression. In this study we aimed to determine what biological processes are driven by Sox9 during this early phase of chondrogenic differentiation. Materials: Sox9 expression in ATDC5 cells was knocked-down by siRNA transfection at the day before chondrogenic differentiation or at day 6 of differentiation. Samples were harvested at 2 hours, and 7 days of differentiation. The transcriptomes (RNA-seq approach) and proteomes (Label-free proteomics approach) were compared using pathway and network analyses. Total protein translational capacity was evaluated with the SuNSET assay, active ribosomes with polysome profiling and ribosome modus with bicistronic reporter assays. Results: Early Sox9 knockdown severely inhibited chondrogenic differentiation weeks later. Sox9 expression during the immediate early phase of ATDC5 chondrogenic differentiation regulated the expression of ribosome biogenesis factors and ribosomal protein subunits. This was accompanied by decreased translational capacity following Sox9 knockdown, and this correlated to lower amounts of active mono- and polysomes. Moreover, cap- versus IRES-mediated translation was altered by Sox9 knockdown. Sox9 overexpression was able to induce reciprocal effects to the Sox9 knockdown. Conclusion: Here we identified an essential new function for Sox9 during early chondrogenic differentiation. A role for Sox9 in regulation of ribosome amount, activity and/or composition may be crucial in preparation for the demanding proliferative phase and subsequent cartilage extracellular matrix-production of chondroprogenitors in the growth plate in vivo.
2021-06-18 | PXD024715 | Pride
Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.
2024-06-16 | PXD046001 | Pride
Project description:Neocortex expansion is largely based on the proliferative capacity of basal progenitors (BPs), which is increased by extracellular matrix (ECM) components via integrin signaling. Here we show that Sox9 drives expression of ECM components and that laminin 211 increases BP proliferation in embryonic mouse neocortex. Examination of Sox9 expression reveals that Sox9 is expressed in BPs of developing ferret and human, but not mouse neocortex. Functional studies by conditional Sox9 expression in the mouse BP lineage demonstrate increased BP proliferation, reduced Tbr2 and induction of Olig2 expression, indicative of premature gliogenesis. Conditional Sox9 expression also results in cell non-autonomous stimulation of BP proliferation followed by increased production of upper-layer neurons. Collectively, our findings demonstrate that Sox9 exerts concerted effects on transcription, BP proliferation, neuron production, and neurogenic as well as gliogenic BP cell fate, suggesting that Sox9 acts a master regulator in the subventricular zone to promote neocortical expansion.
2020-03-27 | GSE134162 | GEO
Project description:Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations, however the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG, and association with the Rela oncofusion in EPN. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.
2022-07-13 | PXD033863 | Pride
Project description:CUT&RUN profiling to compare SOX9 and SOX10 binding in non-transfected A375 cells and A375 cells transfected with SOX9-HA.
2024-05-31 | GSE205044 | GEO
Project description:The transcription factor gene Sox9 plays various roles in development, including differentiation of the skeleton, testes, glia, and heart. Other functions of Sox9 remain enigmatic. Because Sox9 protein regulates expression of target genes, the identification of Sox9 targets should facilitate an understanding of the mechanisms of Sox9 action. To help identify Sox9 targets, we used microarray expression profiling to compare wild-type embryos to mutant embryos lacking activity for sox9a and sox9b, the zebrafish co-orthologs of Sox9. Candidate genes were further evaluated by whole mount in situ hybridization in wild-type and sox9 mutant embryos. Results identified genes expressed in cartilage (col2a1a and col11a2), retina (calb2a, calb2b, crx, neurod, rs1, sox4a and vsx1) and pectoral fin bud (klf2b and EST AI722369) as candidate targets for Sox9. Cartilage is a well-characterized Sox9 target, which validates this strategy, whereas retina represents a novel Sox9 function. Analysis of mutant phenotypes confirmed that Sox9 helps regulate the number of Müller glia and photoreceptor cells and helps organize the neural retina. These roles in eye development were previously unrecognized and reinforce the multiple functions that Sox9 plays in vertebrate development. In each experiment, RNA was isolated from 48h wildtype and sox9a, sox9b double mutant embryos and the gene expression profiles were compared using microarrays. Three biological replicate experiments were performed, and each biological replicate contained a dyeswap.
2010-05-16 | E-GEOD-13482 | biostudies-arrayexpress
Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.
2019-02-06 | GSE101323 | GEO
Project description:Adipocytes arise from commitment and differentiation of adipose precursors in white adipose tissue (WAT). In studying adipogenesis, precursor markers, including Pref-1 and PDGFRα, are used to isolate precursors from stromal vascular fraction of WAT, but the relationship among the markers is not known. Here, we used Pref-1 promoter-rtTA system in mice for labeling Pref-1+ cells and for inducible inactivation of Pref-1 target, Sox9. We show requirement of Sox9 for maintenance of Pref-1+ proliferative, early precursors. Upon Sox9 inactivation, these Pref-1+ cells become PDGFRa+ cells that express early adipogenic markers. Thus, we show for the first time that Pref-1+ cells precede PDGFRa+ cells in the adipogenic pathway and that Sox9 inactivation is required for WAT growth and expansion. Furthermore, we show that, in maintaining early adipose precursors, Sox9 activates Meis1 which prevents adipogenic differentiation. Our study also demonstrates the Pref-1 promoter-rtTA system for inducible gene inactivation in early adipose precursor population.
2018-10-24 | GSE118571 | GEO
Project description:Lineage plasticity plays an important role in the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. Although studies suggest BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal and bipotent phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal/bipotent reprogramming remains unclear. Here we show that the transcription factor SOX9 acts as a determinant for ER– luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical NF-KB signaling. Inactivation of p53 and Rb in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-bipotent reprogramming in vivo. SOX9 deletion inhibits the progression of benign, neoplastic lesions to invasive carcinoma. Furthermore, SOX9 is overexpressed and correlated with shorter relapse-free survival in human BLBC. These data show that ER– LSPC determinant SOX9 acts as a lineage-specific driver for BLBC transformation.
2020-06-09 | GSE135885 | GEO