Universität zu Köln

Valcarcel-Jimenez, Lorea, Rogerson, Connor ORCID: 0000-0002-1425-9668, Yong, Cissy, Schmidt, Christina ORCID: 0000-0002-3867-0881, Yang, Ming ORCID: 0000-0002-7735-7804, Cremades-Rodelgo, Monica, Harle, Victoria, Offord, Victoria, Wong, Kim ORCID: 0000-0002-0984-1477, Mora, Ariane, Speed, Alyson, Caraffini, Veronica, Tran, Maxine Gia Binh, Maher, Eamonn R., Stewart, Grant D., Vanharanta, Sakari, Adams, David J. and Frezza, Christian (2022). HIRA loss transforms FH-deficient cells. Sci. Adv., 8 (42). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Valcarcel-Jimenez, Lorea UNSPECIFIED UNSPECIFIED UNSPECIFIED Rogerson, Connor UNSPECIFIED orcid.org/0000-0002-1425-9668 UNSPECIFIED Yong, Cissy UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Christina UNSPECIFIED orcid.org/0000-0002-3867-0881 UNSPECIFIED Yang, Ming UNSPECIFIED orcid.org/0000-0002-7735-7804 UNSPECIFIED Cremades-Rodelgo, Monica UNSPECIFIED UNSPECIFIED UNSPECIFIED Harle, Victoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Offord, Victoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Wong, Kim UNSPECIFIED orcid.org/0000-0002-0984-1477 UNSPECIFIED Mora, Ariane UNSPECIFIED UNSPECIFIED UNSPECIFIED Speed, Alyson UNSPECIFIED UNSPECIFIED UNSPECIFIED Caraffini, Veronica UNSPECIFIED UNSPECIFIED UNSPECIFIED Tran, Maxine Gia Binh UNSPECIFIED UNSPECIFIED UNSPECIFIED Maher, Eamonn R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stewart, Grant D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vanharanta, Sakari UNSPECIFIED UNSPECIFIED UNSPECIFIED Adams, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frezza, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-688977
DOI:	10.1126/sciadv.abq8297
Journal or Publication Title:	Sci. Adv.
Volume:	8
Number:	42
Date:	2022
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	2375-2548
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language WEB SERVER; EXPRESSION; CANCER; FUMARATE; MUTATIONS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68897