SOX4 and SMARCA4 cooperatively regulate PI3K signaling through transcriptional activation OF TGFBR2 in triple negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA664765 | ENA |
REPOSITORIES: ENA
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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.
2021-03-02 | PXD022811 | Pride
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
Project description:Genomic and proteomic analyses coupled withmechanistic studies identified TGFBR2as a direct transcriptional target of SOX4and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further reportthat SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors,form a previously unreported complex that is requiredto maintain an open chromatin conformationat the TGFBR2regulatory regionsin order tomediateTGFBR2expressionand PI3K signaling.
2021-03-01 | GSE158295 | GEO
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Project description:We knocked down SOX4 in T24 cell and created 3 cell lines: T24-scrambled, T24-SOX4-knockdown and T24-SOX4-rescue and compared gene expression changes SOX4 is a developmental transcription factor that is overexpressed in as many as 23% of bladder cancer patients, but the role of SOX4 in bladder cancer tumorigenesis is not well understood. Given SOX4’s many roles in embryonic development and context-dependent regulation of gene expression, we sought to understand SOX4’s contribution to bladder cancer and to elucidate SOX4 regulated genes that might contribute to tumorigenesis. We employed a CRISPR interference (CRISPRi) method to transcriptionally repress SOX4 expression in T24 bladder cancer cell lines, rescued these cell lines with lentivirally expressed SOX4, and performed whole genome expression profiling. SOX4 knockdown cells exhibited decreased invasive capabilities but no changes in migration or proliferation, while rescue with SOX4 lentiviral vector restored the invasive phenotype. Gene expression profiling revealed 173 high confidence SOX4 regulated genes
2018-08-16 | GSE118572 | GEO
Project description:SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the precise role of SOX4 in cancer progression is not well understood. Here we have either eliminated SOX4 using siRNA or overexpressed a SOX4 cDNA and compared the gene expression patterns against control GFP transfections to identify SOX4 target genes. Data described in manuscript P. Liu et al., Cancer Res 46, 4011 (April 15, 2006) Experiment Overall Design: LNCaP prostate cancer cells were transfected with either a SOX4 cDNA, a pool of SOX4 siRNAs or a control GFP expression vector. Each transfection was performed in duplicate on two separate days. Total RNA was harvested 24 hours post-transfection
2008-11-14 | E-GEOD-11914 | biostudies-arrayexpress
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
Project description:SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the precise role of SOX4 in cancer progression is not well understood. Here we have either eliminated SOX4 using siRNA or overexpressed a SOX4 cDNA and compared the gene expression patterns against control GFP transfections to identify SOX4 target genes. Data described in manuscript P. Liu et al., Cancer Res 46, 4011 (April 15, 2006) Keywords: Gene Expression
2008-11-10 | GSE11914 | GEO
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.
2011-11-18 | GSE31612 | GEO
Project description:We explored the relationship between Myc activity and PI3K signaling in ESCs. Our data demonstrate that Myc and PI3K signaling function cooperatively for supporting pluripotent property of ESCs. Moreover, our data demonstrate that exposure of ESCs to 2i condition render both Myc and PI3K dispensable for preserving ESC status. Effect of PI3K inhibitor, LY4294002 on EBRTcH3 ESCs or their derivatives overexpressing c-Myc (wild-type or T58A mutant) was examined. Effect of LY4294002 on EBRTcH3 ESCs under 2i conditions was also examined. Furthermore, effect of Max expression ablation was compared between ESCs and those overexpressing p110 alpha.
2014-10-30 | E-GEOD-60344 | biostudies-arrayexpress