HIRA loss transforms FH deficient cells [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA838364 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:HIRA loss transforms FH deficient cells
| PRJNA838360 | ENA
Project description:HIRA loss transforms FH deficient cells [RNA-Seq]
| PRJNA833945 | ENA
Project description:Purpose: Identifying transcriptional changes led by Hira loss in FH deficient cells Methods: RNA was extracted from the cell lines using QIAGEN kit folloging the manufacturer instructions. RNA concentrator kit was used to guarantee RNA quality. Results/Conclusion: We identified MYC/E2F1 signatures as the top upregulated ones controlling the oncogenic events occuring in Fh1 and Hira deficient cells.
2022-10-29 | GSE201992 | GEO
Project description:Fumarate Hydratase (FH) is a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle. Germline mutations of FH lead to HLRCC, a cancer syndrome characterised by a highly aggressive form of renal cancer(1). Although HLRCC tumours metastasise rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas(2). How Fh1-deficient cells overcome these tumour suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR/Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the HIRA enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss enables the activation of MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
2022-10-29 | GSE203056 | GEO
Project description:Tumour initiation and progression requires the metabolic rewiring of cancer cells. Fumarate hydratase (FH), a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle, has been identified as a bona fide tumour suppressor . FH loss predisposes to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), a cancer syndrome characterized by the presence of benign tumours of the skin and uterus, and a highly aggressive form of renal cancer. Its loss leads to aberrant accumulation of fumarate, an oncometabolite that drives malignant transformation . Even though the link between FH loss, fumarate accumulation and HLRCC is well-known, the associated tumorigenic mechanism is it is still not fully understood. Indeed, although HLRCC tumours metastasize even when small, Fh1-deficient mice develop premalignant cysts in the kidneys, rather than overt carcinomas. Interestingly, these cysts are positive for the key tumour suppressor p21. Since p21 expression is a central trigger of cellular senescence, it is postulated that this process could be an obstacle for tumorigenesis in Fh1-deficient cells. Consistent with this hypothesis, HLRCC patients harbour the epigenetic suppression of p16, another key player of senescence. Here, we have confirmed that additional oncogenic events independent from a senescence bypass are required to allow full-blown transformation in FH deficient cells. Moreover, a genome wide CRISPR/Cas9 screen identified HIRA as a target that, when ablated, increases proliferation and invasion in Fh1-deficient cells. Moreover, Fh1 and Hira-deficient cells lead to the development of tumours and invasive features in the kidney in vivo. Strikingly, Hira depletion in Fh1 deficient cells controls the activation of a MYC and E2F-dependent transcriptional and metabolic program, which is known to play different oncogenic roles during tumour initiation and progression. Of note, the activation of these programs is independent of H3.3 deposition into the chromatin, known to be controlled by HIRA. Overall, we have identified a novel oncogenic event occurring in FH deficient tumours, which will be instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments.
2022-06-29 | ST002205 | MetabolomicsWorkbench
Project description:Tumour initiation and progression requires the metabolic rewiring of cancer cells. Fumarate hydratase (FH), a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle, has been identified as a bona fide tumour suppressor . FH loss predisposes to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), a cancer syndrome characterized by the presence of benign tumours of the skin and uterus, and a highly aggressive form of renal cancer. Its loss leads to aberrant accumulation of fumarate, an oncometabolite that drives malignant transformation . Even though the link between FH loss, fumarate accumulation and HLRCC is well-known, the associated tumorigenic mechanism is it is still not fully understood. Indeed, although HLRCC tumours metastasize even when small, Fh1-deficient mice develop premalignant cysts in the kidneys, rather than overt carcinomas. Interestingly, these cysts are positive for the key tumour suppressor p21. Since p21 expression is a central trigger of cellular senescence, it is postulated that this process could be an obstacle for tumorigenesis in Fh1-deficient cells. Consistent with this hypothesis, HLRCC patients harbour the epigenetic suppression of p16, another key player of senescence. Here, we have confirmed that additional oncogenic events independent from a senescence bypass are required to allow full-blown transformation in FH deficient cells. Moreover, a genome wide CRISPR/Cas9 screen identified HIRA as a target that, when ablated, increases proliferation and invasion in Fh1-deficient cells. Moreover, Fh1 and Hira-deficient cells lead to the development of tumours and invasive features in the kidney in vivo. Strikingly, Hira depletion in Fh1 deficient cells controls the activation of a MYC and E2F-dependent transcriptional and metabolic program, which is known to play different oncogenic roles during tumour initiation and progression. Of note, the activation of these programs is independent of H3.3 deposition into the chromatin, known to be controlled by HIRA. Overall, we have identified a novel oncogenic event occurring in FH deficient tumours, which will be instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments. Part 2 of this study emoployed a second FH-null clone to complement Part 1 of the study.
2022-07-06 | ST002218 | MetabolomicsWorkbench
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-29 | GSE203057 | GEO
Project description:Genome-wide expression profile in FH-deficient vs FH-competent cells
| PRJNA310748 | ENA
Project description:Comparison of the transcriptome of human kideny cancer cells either wild-type for FH or FH-deficient. The UOK262 cells were isolated from mediastinum metastasis of a HLRCC patient (Yang et al. Cancer Genetics and Cytogenetics, Volume 196, Issue 1, 1 January 2010, Pages 45–55). FH function was restored in the UOK262 by re-expressing the FH transcript from an exogenous plasmid.
2016-09-22 | GSE77538 | GEO
Project description:Fumarate hydratase (FH) is the enzyme in the Krebs cycle, which transforms fumarate to malate. Loss of fumarate hyrdragase leads to hereditary leiomyomatosis and renal cell cancer (HLRCC). The biallelic inactivation has been highly accumulated in FH-deficient cells and is considered a major pro-oncogenic factor for HLRCC tumorigenesis. We used microarrays to understand the global readaptation of cell metabolism of gene expression underlying the truncated Krebs cycle by loss of function of fumarate hydratase. The fumarate hydratase wild type and knock out cells were generated for RNA extraction and hybridization on Affymetrix microarrays.
2014-11-19 | E-GEOD-63438 | biostudies-arrayexpress