Summary of project PR001408

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001408. The data can be accessed directly via it's Project DOI: 10.21228/M8QM6W This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

Project ID: PR001408
Project DOI:doi: 10.21228/M8QM6W
Project Title:Hira Loss Transforms Fh1-Deficient Cells
Project Summary: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.
Institute:CECAD Research Center, University Hospital Cologne
Last Name:Yang
First Name:Ming
Address:Joseph-Stelzmann-Straße 26, CECAD Research Center, Köln, Koeln, 50931, Germany
Email:ming.yang@uni-koeln.de
Phone:+4922147884306

Summary of all studies in project PR001408

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)		 Release
Date		VersionSamplesDownload
(* : Contains raw data)
ST002205 Effect of Hira loss in the metabolic landscape of Fh1-deficient cells Mus musculus CECAD Research Center MS 2022-07-22 1 12 Uploaded data (1.2G)*
ST002218 Effect of Hira loss in the metabolic landscape of Fh1-deficient cells Part 2 Mus musculus CECAD Research Center MS 2022-07-28 1 12 Uploaded data (1.2G)*
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