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Oncostatin M promotes angiogenic and inflammatory responses by inducing histone acetylation in endothelial cells during progression of clear-cell renal cell carcinoma [CUT&Tag]

ABSTRACT: Clear-cell renal cell carcinoma (ccRCC) is the most prevalent and lethal subtype of renal cell carcinoma. Genomic and epigenomic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a crucial early event in ccRCC pathogenesis (~75% of cases). Loss of VHL function leads to dysregulated hypoxia signaling, resulting in an extensive, disorganized, tortuous, and leaky vascular network within ccRCC tissue. It has been shown previously that Oncostatin M (OSM) secreted by the VHL-deficient kidney tubule cells can induce most of these ccRCC-associated vascular phenotypes which in turn promote tumor cell proliferation, immune cell infiltration, and metastasis. The influence of OSM to ECs could induce extensive and long-lasting transcriptomic changes in ECs although these ECs did not harbor any genomic mutations. Further studies indicate that OSM specifically activates endothelial cells (ECs) by inducing acetylation of histone 3 at lysine 14 (H3K14ac). Thus, we performed a variant of chromatin immunoprecipitation analysis, the Cleavage Under Targets and Tagmentation (CUT&TAG) sequencing, on OSM-treated and untreated ECs labeled with anti-H3K14ac antibody to validate the role of H3K14ac in the activation of ECs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271723 | GEO | 2025/08/27

REPOSITORIES: GEO

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Oncostatin M promotes angiogenic and inflammatory responses by inducing histone acetylation in endothelial cells during progression of clear-cell renal cell carcinoma

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent and lethal subtype of renal cell carcinoma. Genomic and epigenomic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a crucial early event in ccRCC pathogenesis (~75% of cases). Loss of VHL function leads to dysregulated hypoxia signaling, resulting in an extensive, disorganized, tortuous, and leaky vascular network within ccRCC tissue. It has been shown previously that Oncostatin M (OSM) secreted by the VHL-deficient kidney tubule cells can induce most of these ccRCC-associated vascular phenotypes which in turn promote tumor cell proliferation, immune cell infiltration, and metastasis. The influence of OSM to ECs could induce extensive and long-lasting transcriptomic changes in ECs although these ECs did not harbor any genomic mutations. The observations suggest a novel interaction mechanism between tumor cells and stromal cells, in which OSM emanating from the tumor cells may induce transcriptomic changes in ECs via epigenetic modification. To further explore the underlying mechanisms, we directly treated HMEC-1, a microvascular endothelial cell, with recombination OSM with or without histone acetylation inhibitors. The total mRNA of these samples was then performed mRNA Sequencing (mRNA-Seq).

2025-08-27 | GSE271554 | GEO

Changes of transcriptome in endothelial cells from kidney with tubule-specific conditional Vhlh gene knockout (Hoxb7-Cre-GFP; VhlhloxP/loxP), compared with wild-type.

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of RCC in which more than 80% of ccRCC cases are associated with early inactivation of von Hippel-Lindau (VHL) tumor suppressor gene. We have generated a knockout mouse strain in which mouse allele of VHL (Vhlh) is conditionally deleted in the kidney epithelium (cortical tubules, collecting ducts and ascending Loops of Henle). These knockout mice showed high penetrance of inflammation and fibrosis in the kidney in addition to hyperplasia and the appearance of transformed clear cells. These results support the concept of tumor-promoting inflammation. Surprisingly, we found that the expression of pJNK, a marker of inflammation, was expressed in endothelial cells (ECs) in Vhlh mutant tissue although the knockout was in epithelial cells not in endothelial cells. The result indicated the important role of ECs in the initiation tumor progression. Therefore, the aim of this study is to investigate the molecular changes of ECs in the VHL mutant microenvironment.

2021-06-18 | GSE159754 | GEO

RNAseq transcriptome analysis of THP-1 macrophages activated by VHL-deficient kidney tubule cells

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.

2022-03-12 | GSE183976 | GEO

Gene expression data from the 786-O renal cell carcinoma cell line and its metastatic derivatives.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression profiles of 786-O renal cell carcinoma cells and metastatic subpopulations isoloated by in vivo selection in immunocomrpmized mice. The derivatives are significantly enriched in the metastatic propensity as measure by experimental metastasis assays.

2012-12-05 | E-GEOD-32295 | biostudies-arrayexpress

Generation of Patient-Matched Malignant and Normal Primary Cell Cultures from Clear Cell Renal Cell Carcinoma Patients

Project description:Transcriptome profiling of de novo-derived ccRCC cell cultures and their matching parental tumours. VHL-mutant and VHL wild-type cultures were established by isolating CA9+ and CA9- cells from tumor samples using FACS. RNASeq expression profiling of 18 renal cell carcinoma samples, including 6 patient tumours, 6 VHL mutant and 6 VHL WT derivative cell cultures

2016-06-01 | E-GEOD-74958 | biostudies-arrayexpress

VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma

Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bound VHL only when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased ZHX2 amount and nuclear localization. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated ChIP-Seq and microarray analysis showed that ZHX2 promoted NF-kB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

2018-07-19 | GSE109953 | GEO

Gene expression changes in response to VHL-reintroduction in metastatic 786-M1A cells.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from metastatic 786-M1A cells with and without reintroduced HA-VHL. The empty vector, pBabe-puro, was used as control.

2012-12-05 | E-GEOD-32297 | biostudies-arrayexpress

Next Generation Sequencing of 786-O-Ctrl and786-O-VHL Transcriptomes

Project description:Inactivation of the E3 ubiquitin ligase protein von Hippel-Lindau (VHL) is critical to clear cell renal cell carcinomas (ccRCC) and VHL syndrome. VHL loss leads to stabilization of hypoxia-inducible factor α (HIFα) and other substrate proteins, which may drive various tumor-promoting pathways. This process is likely reversible, because even in the highly aggressive human VHL-deficient ccRCC cell line 786-O, restoring VHL expression almost completely abolishes orthotopic tumor formation in immuno-deficient mice. This result highlights the potential of treating ccRCC by re-expressing VHL with gene therapy. However, there is inadequate understanding of the consequence of VHL restoration at the molecular level. Here, we reinstalled VHL expression in 786-O and performed transcriptome, proteome and ubiquitome profiling to assess the molecular impact.

2021-10-18 | GSE186013 | GEO

Gene expression changes in 786-O cells in response to 5DC treatment.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression data from 786-O cells after 3-day treatment with 100uM 5’-aza-deoxycytidine (5DC) or vehicle (DMSO).

2012-12-05 | E-GEOD-32298 | biostudies-arrayexpress

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2012-12-05 | E-GEOD-32299 | biostudies-arrayexpress

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