Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of histone demethylase JARID1C triggers genomic instability in cancer.

ABSTRACT: Chromatin remodelers are recurrently mutated in cancer. Among these, JARID1C, (KDM5C) a histone demethylase, is frequently inactivated in clear cell renal cell carcinoma (ccRCC) patients. How the genetic inactivation of JARID1C leads to cancer remains largely unknown. Here we report that JARID1C binds to broad chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), an histone mark enriched in heterochromatin. We also found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established and novel players of heterochromatin assembly, such as SUV39H1 and HP1 and the CUL4 complex adaptor protein DDB1, respectively. To safeguard the genome, transcription on heterochromatin is tightly suppressed. JARID1C inactivation leads to the unrestrained expression of heterochromatic ncRNAs, that in turn trigger genomic instability. Remarkably, ccRCC patients harbouring JARID1C mutations show aberrant ncRNA expression and increased genomic rearrangements when compared with tumors endowed with other genetic lesions. Together, these data suggest that the inactivation of JARID1C in renal cancer leads to heterochromatin disruption and to aggressive, genomically rearranged ccRCCs, shedding light on a novel mechanism underlying genomic instability in sporadic cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73267 | GEO | 2015/11/09

SECONDARY ACCESSION(S): PRJNA296489

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Loss of histone demethylase JARID1C triggers genomic instability in cancer.

Project description:Chromatin remodelers are recurrently mutated in cancer. Among these, JARID1C, (KDM5C) a histone demethylase, is frequently inactivated in clear cell renal cell carcinoma (ccRCC) patients. How the genetic inactivation of JARID1C leads to cancer remains largely unknown. Here we report that JARID1C binds to broad chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), an histone mark enriched in heterochromatin. We also found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established and novel players of heterochromatin assembly, such as SUV39H1 and HP1 and the CUL4 complex adaptor protein DDB1, respectively. To safeguard the genome, transcription on heterochromatin is tightly suppressed. JARID1C inactivation leads to the unrestrained expression of heterochromatic ncRNAs, that in turn trigger genomic instability. Remarkably, ccRCC patients harbouring JARID1C mutations show aberrant ncRNA expression and increased genomic rearrangements when compared with tumors endowed with other genetic lesions. Together, these data suggest that the inactivation of JARID1C in renal cancer leads to heterochromatin disruption and to aggressive, genomically rearranged ccRCCs, shedding light on a novel mechanism underlying genomic instability in sporadic cancers. We performed ChIP-sequencing for KDM5C, H3K9me3, H3K4me1 and H3K4me3 in Caki-1 untreated cells. Platform HiSeq2500.

2015-11-09 | E-GEOD-73267 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

Project description:Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer is often associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), leading to stable expression of hypoxia inducible factors, HIF1α and HIF2α. Although HIF1α functions as a tumor suppressor gene, majority of ccRCCs constitutively express HIF1α, stratifying VHL-deficient ccRCCs into groups which express either both HIF1α and HIF2α (H1H2) or HIF2α exclusively (H2). MicroRNA (miRNA) profiling performed in these two ccRCC subtypes to identify novel molecular mechanisms. ccRCCs were classified into H1H2 and H2 subtypes by immunohostochemical staining of H1F1α and H1F2α expression. Five H1H2 tumor samples and eight H2 tumor samples were used for the study. Matched adjacent normal renal tissues were used as respective controls.

2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

2013-09-30 | GSE47582 | GEO

Genome-wide microRNA expression analysis of clear cell Renal Cell Carcinoma by next generation deep sequencing

Project description:MicroRNAs (miRNAs), non-coding RNAs regulating gene expression, are frequently aberrantly expressed in human cancers. Next-generation deep sequencing technology enables genome-wide expression profiling of known miRNAs and discovery of novel miRNAs at unprecedented quantitative and qualitative accuracy. Deep sequencing was performed on 22 fresh frozen clear cell renal cell carcinoma (ccRCC), 11 non-tumoral renal cortex (NRC) samples and 2 ccRCC cell lines (n=35). The 22 ccRCCs patients belonged to 3 prognostic sub-groups, i.e. Those without disease recurrence, with recurrence and with metastatic disease at diagnosis Deep sequencing was performed on 22 fresh frozen clear cell renal cell carcinoma (ccRCC), 11 non-tumoral renal cortex (NRC) samples and 2 ccRCC cell lines (n=35). The 22 ccRCCs patients belonged to 3 prognostic sub-groups, i.e. Those without disease recurrence, with recurrence and with metastatic disease at diagnosis.

2012-06-21 | E-GEOD-37616 | biostudies-arrayexpress

Lineage factor-dependent signalling by kidney cancer-associated genetic alteration

Project description:As shown by large-scale human genetic data, cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analysis of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common clear cell renal cell carcinoma (ccRCC)-causing genetic alterations in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL). VHL loss, observed in ~90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3. These results demonstrate that transcriptional lineage factors are essential for the expression of canonical oncogenes and they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants

2022-03-14 | PXD029522 | Pride

Towards a CRISPR-Based Mouse Model of Vhl-deficient Clear Cell Kidney Cancer: Initial Experience and Lessons Learned

Project description:CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard of care agent, axitinib. RNAseq analysis was utilized to evaluate the expression profile produced by the targeted loss of Vhl, Pbrm1, Keap1 and Tsc1 in these mouse tumors. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2-independent.

2024-08-24 | GSE275231 | GEO

Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma

Project description:Previously, we have reported that genomic loss of 14q occurs more frequently in high grade clear cell renal cell carcinomas (ccRCCs) than low grade ones and shows a significant impact on the expression levels of genes located on this region, suggesting that the genes located on the region and downregulated by the loss may be involved in the malignant transformation of ccRCCs. Here, among the genes located on the minimal common region of 14q loss, we found that 6 were significantly downregulated in high grade ccRCCs due to copy number loss. Using the data set from The Cancer Genome Atlas (TCGA) Research Network, downregulation of one out of the 6 genes, WDR20, was significantly associated with poorer prognosis for the patients with ccRCC, suggesting that downregulation of WDR20 may be involved in the malignant transformation of ccRCC. In functional assays, exogeneous WDR20 significantly inhibited growth and induced apoptosis in RCC cell lines. Interestingly, the phosphorylation levels of ERK and AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by the exogeneous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs in part through the activation of ERK and AKT pathways. Downregulated expression levels of genes in minimal common region due to 14q loss. Expression levels of 6 genes were determined by microarray analysis and compared between normal kidney tissues (normal, n=16), low grade (low, n=16) and high grade (high, n=16) ccRCCs. The expression level (log2) normalized by the median expression level for the 16 normal samples.

2016-08-09 | E-GEOD-71963 | biostudies-arrayexpress

Genomic profiling of primary and metastatic clear cell renal cell carcinoma by array-based comparative genomic hybridization.

Project description:In this study, we investigated CNAs of 20 primary clear cell renal cell caricinomas (ccRCCs), 20 corresponding metastases and another subsets of 30 primary ccRCCs by 44k oligonucleotide-based array comparative genomic hybridization (array CGH). 20 primary ccRCCs, 20 corresponding metastases and another subsets of 30 primary ccRCCs.

2014-10-16 | E-GEOD-43477 | biostudies-arrayexpress

HAVCR/KIM-1 activates the IL-6/STAT-3 Pathway in ccRCC and Determines Tumor Progression and Patient Outcome

Project description:Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell (ccRCC) is the most common and aggressive subtype of renal cancer. Commonly asymptomatic, more than 30% of ccRCCs are diagnosed when they are already metastatic resulting in a 95% mortality rate and one-third of organ-confined cancers treated by nephrectomy develop metastasis during the follow-up. Diagnosis and monitoring requires expensive and frequent imaging examinations; thereby, finding of diagnostic and prognostic biomarkers to screen, diagnose and monitor renal cancers are clearly needed. Hepatitis A virus receptor/kidney injury molecule 1 (HAVCR1/KIM-1) gene has been claimed to be a susceptibility gene for ccRCC and HAVCR1/KIM-1 ectodomain shedding a predictive biomarker of tumor progression.

2020-09-27 | E-MTAB-2071 | biostudies-arrayexpress

HIF-1α and HIF-2α differently regulate tumour development, metabolism and inflammation of clear cell renal cell carcinoma in mice

Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.

2020-07-02 | PXD016630 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data