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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.

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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

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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

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

2021-03-02 | PXD022811 | Pride

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

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

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