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HIRA loss transforms FH deficient cells [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE201992 | GEO | 2022/10/29

REPOSITORIES: GEO

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HIRA loss transforms FH deficient cells [ChIP-Seq]

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.

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HIRA loss transforms FH deficient cells

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The role of HIF in FH-associated renal neoplasia

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The role of HIF in FH-associated renal neoplasia

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

<i>HIRA</i> loss transforms <i>FH</i>-deficient cells.

Project description:Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of FH lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How Fh1-deficient cells overcome these tumor-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 histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates 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.

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HIRA loss transforms FH deficient cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-29 | GSE203057 | GEO

Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-Ribose Polymerase inhibitors and low-dose alkylating chemotherapy

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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.

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