VHL restoration alters cis-regulatory landscape
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102095 | GEO | 2017/08/22
SECONDARY ACCESSION(S): PRJNA396574
REPOSITORIES: GEO
Similar Datasets
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
Project description:VHL loss is the most common genetic alteration event in ccRCC. VHL loss stabilizes hypoxia-inducible factor-2 alpha (HIF2a). We compared the changes in transcriptomics profiles after VHL restoration or HIF2a siRNA knockdown in 786-O cells.
2017-08-22 | GSE102097 | GEO
Project description:VHL loss is the most common genetic alteration event in ccRCC. We profiled histone modifications from VHL-deficient ccRCC primary tumors and cell lines. We show that ccRCCs exhibit a pervasive gain of enhancers around hypoxic and metabolic transcriptional targets. Motif analysis using HOMER revealed significant enrichment of AP-1, ETS, NFĸB and HIFα in tumor enhancers. We generated ChIP-seq binding data for c-Jun, ETS1, NFĸB, and P300, a histone acetyltransferase, in 786-O cells. ChIP-seq profiles of HIF2α and HIF1β in 786-O were already generated previously (GSE34871)
2017-08-22 | GSE86092 | GEO
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
Project description:786-0 is a cell line derived from a clear cell renal carcinoma. Previous studies have shown that the 786-O cell line harbors an inactivating mutation in the von-Hippel Lindau (VHL) gene. Mutations in the VHL gene occur in the majority of sporadic clear cell renal cell. To determine how inactivation of the VHL affects cellular functions, we created a derivative of 786-0, which we call 786-VHL in which a functional allele of VHL has been introduced back into the 786-O cell line. The renal cell carcinoma cell line 786-0, which harbors a mutated allele of VHL, was compared to a cell line derived from 786-0, termed 786-VHL, that contains a functional allele of VHL. Genes whose expression characteristics were dependent on functional VHL were identified.
2010-06-23 | E-GEOD-22256 | biostudies-arrayexpress
Project description:786-0 is a cell line derived from a clear cell renal carcinoma. Previous studies have shown that the 786-O cell line harbors an inactivating mutation in the von-Hippel Lindau (VHL) gene. Mutations in the VHL gene occur in the majority of sporadic clear cell renal cell. To determine how inactivation of the VHL affects cellular functions, we created a derivative of 786-0, which we call 786-VHL in which a functional allele of VHL has been introduced back into the 786-O cell line.
2010-06-10 | GSE22256 | GEO
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
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
Project description:The human renal cancer cell line 786-0 was transfected with 3 vectors allowing the doxycycline-inducible expression of 1) the full length wild type sequence of VHL: 786-0 VHL WT, VHL+/+, 2) the R167Q mutant : 786-0 R167Q, VHL mutated, 3) the empty vector : 786-0 EV, VHL-/-. The aim of the study was to examine whether the VHL-R167Q mutation, which is associated with a high risk of developping clear cell renal carcinomas, could impact the plasticity of renal carcinoma cells.
2021-12-09 | E-MTAB-11168 | biostudies-arrayexpress
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.
2012-12-05 | GSE32297 | GEO