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Identification of SOX4 novel transcriptional targets

ABSTRACT: The SOX4 gene belongs to a family of transcription factors and we previously unveiled SOX4 gene amplification and over-expression in a subset of lung cancers, indicating it may constitute a driver oncogene. Here, we searched for SOX4 transcriptional targets and investigate their involvement in lung development and carcinogenesis. We abrogated SOX4 expression in the NIH-H522 lung cancer cell line, carrying SOX4 amplification and over-expression, using an inducible short-hairpin system. Global analysis of gene expression identified about 90 genes down-regulated after SOX4 abrogation many of them related to neural development. We also demonstrated recruitment of SOX4 to many of these promoters, evidencing their nature as direct transcriptional targets of SOX4. Most of these transcripts were significantly increased in lung cancer cells with ectopic SOX4 over-expression and in lung tumors with high levels of SOX4. Conversely, many of them exhibited significant low expression levels in embryonic fibroblasts from Sox4-/- mice. We generated H522-derived cells that down-regulate SOX4 in an inducible manner. The H522 cells were transfected with a tetracycline (tet) repressor expression construct and a tet-repressor-controlled expression vector (tet-on) containing a shSOX4. An stable clone, H522Tr-shSOX4-1, which down-regulate SOX4 expression by 90%, 48 hours after adding doxycycline, was chosen for further analysis. To determine the gene expression profile characteristic of SOX4 depleted expression we compared the global gene expression of the parental H522 cells to the H522Tr-shSOX4-1 cells at 0, 24 and 96 hrs after inducing the shSOX4 with doxycycline using the Whole Human Genome Microarray from Agilent.

ORGANISM(S): Homo sapiens

SUBMITTER: Castillo SD

PROVIDER: S-ECPF-GEOD-31612 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Identification of SOX4 novel transcriptional targets.

Project description:The SOX4 gene belongs to a family of transcription factors and we previously unveiled SOX4 gene amplification and over-expression in a subset of lung cancers, indicating it may constitute a driver oncogene. Here, we searched for SOX4 transcriptional targets and investigate their involvement in lung development and carcinogenesis. We abrogated SOX4 expression in the NIH-H522 lung cancer cell line, carrying SOX4 amplification and over-expression, using an inducible short-hairpin system. Global analysis of gene expression identified about 90 genes down-regulated after SOX4 abrogation many of them related to neural development. We also demonstrated recruitment of SOX4 to many of these promoters, evidencing their nature as direct transcriptional targets of SOX4. Most of these transcripts were significantly increased in lung cancer cells with ectopic SOX4 over-expression and in lung tumors with high levels of SOX4. Conversely, many of them exhibited significant low expression levels in embryonic fibroblasts from Sox4-/- mice. We generated H522-derived cells that down-regulate SOX4 in an inducible manner. The H522 cells were transfected with a tetracycline (tet) repressor expression construct and a tet-repressor-controlled expression vector (tet-on) containing a shSOX4. An stable clone, H522Tr-shSOX4-1, which down-regulate SOX4 expression by 90%, 48 hours after adding doxycycline, was chosen for further analysis. To determine the gene expression profile characteristic of SOX4 depleted expression we compared the global gene expression of the parental H522 cells to the H522Tr-shSOX4-1 cells at 0, 24 and 96 hrs after inducing the shSOX4 with doxycycline using the Whole Human Genome Microarray from Agilent.

2011-11-18 | E-GEOD-31612 | biostudies-arrayexpress

Identification of SOX4 novel transcriptional targets.

2011-11-18 | GSE31612 | GEO

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

Project description: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 type of tumor. 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 can thereby promote 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 patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

| S-EPMC6277201 | biostudies-literature

Identification of direct transcriptional targets of V600EBRAF/MEK in melanoma

Project description:A375P melanoma cells were treated with 1uM of the MEK inhibitor PD184352 or 0.4uM of the V600EBRAF inhibitor PLX4720 for 2hr, 6hr and 24hrs. DMSO treatment for 2hr, 6hr and 24hrs serves as the negative control Triplicate experiments were performed for DMSO, PD184352 and PLX4720 treatment at 3 timepoints - 2, 6, 24hrs.

| S-ECPF-GEOD-17089 | biostudies-other

Identification of Arx transcriptional targets in the developing basal forebrain.

Project description:Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.

| S-EPMC2581427 | biostudies-literature

Microarray identification of novel downstream targets of FoxD4L1/D5, a critical component of the neural ectodermal transcriptional network.

Project description:FoxD4L1/D5 is a forkhead transcription factor that functions as both a transcriptional activator and repressor. FoxD4L1/D5 acts upstream of several other neural transcription factors to maintain neural fate, regulate neural plate patterning, and delay the expression of neural differentiation factors. To identify a more complete list of downstream genes that participate in these earliest steps of neural ectodermal development, we carried out a microarray analysis comparing gene expression in control animal cap ectodermal explants (ACs), which will form epidermis, to that in FoxD4L1/D5-expressing ACs. Forty-four genes were tested for validation by RT-PCR of ACs and/or in situ hybridization assays in embryos; 86% of those genes up-regulated and 100% of those genes down-regulated in the microarray were altered accordingly in one of these independent assays. Eleven of these 44 genes are of unknown function, and we provide herein their developmental expression patterns to begin to reveal their roles in ectodermal development.

| S-EPMC3057538 | biostudies-literature

Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43.

Project description:Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize extensively in the embryo including the atrioventricular and outflow tract cushion mesenchyme and a small area of interventricular myocardium. Tbx3, SOX4, and SOX2 ChIP data, identify a region in intron 1 of Gja1 bound by all tree proteins and subsequent ChIP experiments verify that this sequence is bound, in vivo, in the developing heart. In a luciferase reporter assay, this element displays a synergistic antagonistic response to co-transfection of Tbx3 and Sox4 and in vivo, in zebrafish, drives expression of a reporter in the heart, confirming its function as a cardiac enhancer. Mechanistically, we postulate that Sox4 is a mediator of Tbx3 transcriptional activity.

| S-EPMC3214269 | biostudies-literature

SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2.

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.

| S-EPMC8035213 | biostudies-literature

Identification of transcriptional targets of FGF20.

Project description:Identification of transcriptional targets of FGF20.

| PRJNA433812 | ENA

Identification of novel vascular targets in lung cancer.

Project description:BackgroundLung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer.MethodsEnzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology.ResultsBioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation.ConclusionsThe identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development.

| S-EPMC4453649 | biostudies-literature

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