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Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

ABSTRACT: The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the tumor-type. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and thereby promotes tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in breast cancer patients. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role by promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99256 | GEO | 2020/01/01

REPOSITORIES: GEO

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Differential gene expression in Hep3B and Hep3B SOX4-/- cells

Project description:Overexpression of SOX4 in various kinds of cancers specimen was associated with poor prognosis of patients; however, the role of SOX4 in angiogenesis or tumor microenvironment modulation remains unclear. Therefore the endogenous SOX4 was knockout and the differential gene expression between Hep3B and Hep3B SOX4-/- cells were examined via genechip. We found that the differentially expressed genes, EzH2, a SOX4-associated partner, and CXCL12, were repressed in Hep3B SOX4-/- cells compared with parental Hep3B; these results were further assessed via qRT-PCR in Hep3B SOX4-/- versus Hep3B cells.

2020-12-01 | GSE141909 | GEO

Sox4 knockdown in ACC3 cells

Project description:Sox4 is upregulated in adenoid cystic carcinoma (ACC). The ACC3 cell line is the most widely available cell culture model system of this tumor type. RNAi mediated knockdown of Sox4 in ACC3 cells induces apoptosis. Since Sox4 is a transcription factor, it is hypothesized that this apoptotic phenotype is due to changes in transcription from genes under Sox4 control.This experiment was designed to find candidate genes whose expression levels change after Sox4 knockdown that could contribute to the pro-apoptotic phenotype. Keywords: gene knockdown

2006-07-28 | GSE4225 | GEO

SMAD3 and SOX4 binding profiling in human breast cell lines

Project description:In order to identify genes co-bound by SOX4 and SMAD3 in the context of breast cancer, different breast cell lines (HMLEs, MDA-MB-231 or HCC-1954) were used. Due to low endogenous expression levels for SOX4 in HMLEs in untreated conditions, doxycycline-dependent SOX4 overexpression was obtained by transducing HMLE cells with pIINDUCER21-SOX4 vector..Cells were plated and SOX4 and SMAD3 chromatine-immunoprecipitation was performed in untreated conditions, TGF-beta (2.5ng/ml), doxycycline (0.5ug/ml) or both as indicated. Genome-wide binding sites for SOX4 and SMAD3 was identified in HMLEs, MAD-MB-231 and HCC-1954 cells.

2018-06-11 | GSE104760 | GEO

SOX4 AND SMARCA4 COOPERATIVELY REGULATE PI3K SIGNALING THROUGH TRANSCRIPTIONAL ACTIVATION OF TGFBR2 IN TRIPLE NEGATIVE BREAST CANCER

Project description:Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression. Kinase enrichment proteomic analysis was performed using HCC1143 breast cancer cells treated with a control siRNA pool or a pool targeting SOX4 in biological triplicate to evaluate the effects on the functional kinome.

2021-03-03 | PXD022596 | Pride

TRPM7 maintains mesenchymal phenotype of breast cancer cells by tensional regulation of SOX4 (SOX4 shRNA)

Project description:Analysis of the effect of shRNA-mediated knockdown of SOX4 on global gene expression levels in MDA-MB-231 human breast cancer cells. Results were used for the identification of overlapping up- and downregulated genes in TRPM7 + SOX4 shRNA MDA-MB-231 cells

2015-06-16 | GSE63957 | GEO

Sox4 null mice e12.5 pancreas

Project description:The purpose of this experiment was to assess global changes in gene expression pattern in the pancreas from Sox4-/- embryos vs. pancreas from Sox4 wild-type embryos at embryonic day 12.5. [Sox4 gene knock-out (Schilham, M. W. et al. (1996) Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380, 711-4.)] Embryonic pancreases from homozygous mutants and their wild-type littermates were harvested. Total RNA was isolated amplified using a linear amplification kit and used to prepare the hybridization samples through indirect labeling. Keywords = Pancreas Sox4 null e12.5 Keywords: parallel sample

2005-12-01 | GSE2539 | GEO

Unraveling the Sox4-orchestrated pro-B cell differentiation program: Intricate roles of the RAG and CK1ε genes (ChIP-Seq)

Project description:Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells. One sample of BAP-Sox4 bioChIP DNA and one sample of BAP-Sox4 input chromatin DNA were used.

2014-07-02 | E-GEOD-50066 | biostudies-arrayexpress

RNA-sequencing of mouse mammary tumor organoids that were modified to generate knockout lines for SOX4

Project description:The transcription factor SOX4 is widely expressed during development and is essential to maintain progenitor pools in a variety of organs. In breast cancer SOX4 has been shown to be associated with poor survival and increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a plastic manner that is dependent on the cellular and epigenetic context. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model. CRISPR-mediated loss of SOX4 led to a strong impairment in growth of primary mammary tumors and subsequent metastases through an EMT-independent mechanism. Instead, SOX4 is required for inhibiting differentiation by controlling genes that are highly activated in foetal mammary stem cells (fMaSC). These SOX4-dependent genes are associated with cell cycle progression, DNA biosynthesis, RNA processing and ribosome biogenesis suggesting that SOX4 controls active cycling of tumor cells. Analysis of genes co-expressed with SOX4 in the TCGA and METABRIC studies revealed that these cell cycle-related genes correlate with SOX4 expression in human tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated proliferative state.

2021-09-30 | GSE153190 | GEO

Unraveling the Sox4-orchestrated pro-B cell differentiation program: Intricate roles of the RAG and CK1Îµ genes (RNA array)

Project description:One of the main objective of this study is to identify Sox4 controlled gene networks and their roles in progenitor B cells. Commitment of hematopoietic stem cells to B lineage precursors and development of B lineage precursors into mature B cells is attained through the coordinated function of multiple signaling networks, which are in turn controlled through stringent functioning of stage-specific transcription factors. Here, we describe the essential role of Sox4, an HMG (high mobility group)-box-containing transactivator, in B cell development. In the absence of Sox4, differentiation from pre-pro B to pro-B, from pro-B fraction B to pro-B fraction C and further to the immature B cell stage was severely impaired. Loss of differentiation was associated with reduced expression of Rag1 and Rag2 and markedly reduced DJ (diverse, joining) and VDJ (variable DJ) recombination at immunoglobulin heavy chain gene loci. We uncovered Sox4-regulated transcriptional circuits and a landscape of Sox4-chromatin interactions in pro-B cells. Sox4 ensured the negative regulation of Wnt signaling, which is critical for self-renewal of hematopoietic stem cells and early progenitors, by inducing one of its downstream effectors, casein kinase 1 epsilon. Our findings suggest that Sox4 orchestrates a unique transcriptional program and coordinates multilevel control in the differentiation of early-stage B cells. Total RNA isolated from triplicate samples were used for each cell type. Gene expression signatures were compared between Sox4fl/fl and Sox4fl/fl SE-Cre progenitor B cells (Loss-of-function array); p190 Bcr-Abl-immortalized Sox4fl/fl SE-Cre HA and Sox4fl/fl SE-Cre HA-Sox4 progenitor B cells (Gain-of-function array).

2014-07-02 | E-GEOD-50065 | biostudies-arrayexpress

SOX4 AND SMARCA4 COOPERATIVELY REGULATE PI3K SIGNALING THROUGH TRANSCRIPTIONAL ACTIVATION OF TGFBR2 IN BASAL LIKE BREAST CANCER

2021-03-02 | PXD022811 | Pride

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