Summary of Study ST002218

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, 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.


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Study IDST002218
Study TitleEffect of Hira loss in the metabolic landscape of Fh1-deficient cells Part 2
Study SummaryTumour 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.
CECAD Research Center
Last NameYang
First NameMing
AddressJoseph-Stelzmann-Straße 26, Köln, Koeln, 50931, Germany
Submit Date2022-07-06
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2022-07-28
Release Version1
Ming Yang Ming Yang application/zip

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Subject type: Cultured cells; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Treatment
SA211943LV17-09Fh1-/- CL1 Cas9
SA211944LV17-07Fh1-/- CL1 Cas9
SA211945LV17-08Fh1-/- CL1 Cas9
SA211946LV17-12Fh1-/- CL1 sg1Hira
SA211947LV17-11Fh1-/- CL1 sg1Hira
SA211948LV17-10Fh1-/- CL1 sg1Hira
SA211937LV17-01Fh1 fl/fl Cas9
SA211938LV17-03Fh1 fl/fl Cas9
SA211939LV17-02Fh1 fl/fl Cas9
SA211940LV17-06Fh1 fl/fl sg1Hira
SA211941LV17-04Fh1 fl/fl sg1Hira
SA211942LV17-05Fh1 fl/fl sg1Hira
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