The role of HIF in FH-associated renal neoplasia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29988 | GEO | 2011/10/24
SECONDARY ACCESSION(S): PRJNA140707
REPOSITORIES: GEO
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Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice. We intercrossed Fh1/Hif1a mice with kidney specific cre recombinase (Ksp-Cre) and analysed kidney cyst formation. RNA was extracted from cysts from 4xFh1 KO, 4xFh1/Hif-1a KO and 4 control mice. For each comparison littermates were used and the animals were aged 15 weeks i.e. early cystic disease.
2011-10-23 | E-GEOD-29988 | biostudies-arrayexpress
Project description:Fumarate hydratase (FH) mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC). We have conditionally inactivated the murine ortholog (Fh1) in renal tubular epithelial cells in order to generate an in vivo model of HLRCC. Fh1 knockout mice recapitulates important aspects of HLRCC including the development of renal cysts that overexpress hypoxia inducible factor alpha (Hifa) and Hif-target genes. We used microarrays to detail the global programme of gene expression underlying cyst development in Fh1 knockout mice and identified distinct classes of up-regulated genes during this process. Keywords: gene expression, comparison (wild-type n=3 vs knockout n=3)
2010-12-22 | GSE10989 | GEO
Project description:Fumarate hydratase (FH) mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC). We have conditionally inactivated the murine ortholog (Fh1) in renal tubular epithelial cells in order to generate an in vivo model of HLRCC. Fh1 knockout mice recapitulates important aspects of HLRCC including the development of renal cysts that overexpress hypoxia inducible factor alpha (Hifa) and Hif-target genes. We used microarrays to detail the global programme of gene expression underlying cyst development in Fh1 knockout mice and identified distinct classes of up-regulated genes during this process. Keywords: gene expression, comparison (wild-type n=3 vs knockout n=3) Renal epithelial tissue was macro-dissected from Fh1 knockout mice and sex-matched litter mate control disease-free animals for RNA extraction and hybridization on Affymetrix microarrays.
2010-12-22 | E-GEOD-10989 | biostudies-arrayexpress
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: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: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:Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (HLRCC, Hereditary Leiomyomatosis and Renal Cell Cancer (MM ID # 605839)). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-a stabilization. Paradoxically, FH mutation differs from other HIF-a stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes. We demonstrated that AKR1B10 is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH-null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2. Expression profiling renal normal and tumor tissue
2011-10-17 | E-GEOD-26574 | biostudies-arrayexpress
Project description:Fumarate Hydratase (FH) is an enzyme of the Tricarboxilic Acid Cycle (TCA) that catalyzes the conversion of fumarate into malate. In the last decade, studies have revealed FH as a bona fide tumour suppressor whose mutations cause Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate. Yet, whilst the long-term consequences of FH loss have been extensively described, the acute response to FH loss has not been investigated due, in part, to the lack of a suitable model. Here, we generated a new inducible mouse model to investigate the chronology of the murine homologue of FH, Fh1, loss in the adult kidney.
2023-02-17 | GSE183745 | GEO
Project description:Mycoplasmoides pneumoniae FH strain:FH Genome sequencing
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