title: Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes.
abstract: Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelicFHinactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates howFHinactivation can endow cells with a growth advantage.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
authors.forename: Michael John
authors.identifier: http://orcid.org/0000-0003-3095-4641
authors.initials: MJ
authors.lastname: Kerins
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Ajay Amar
authors.initials: AA
authors.lastname: Vashisht
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
authors.forename: Benjamin Xi-Tong
authors.initials: BX
authors.lastname: Liang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
authors.forename: Spencer Jordan
authors.initials: SJ
authors.lastname: Duckworth
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
authors.forename: Brandon John
authors.initials: BJ
authors.lastname: Praslicka
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: James Akira
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA ooi@pharmacy.arizona.edu.
authors.forename: Aikseng
authors.initials: A
authors.lastname: Ooi
mesh_terms: D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005293:Ferritins / Q000235:genetics*; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D005649:Fumarate Hydratase / Q000378:metabolism*; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000737:chemistry / Q000378:metabolism; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018231:Leiomyomatosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D019802:Succinic Acid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D005650:Fumarates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005293:Ferritins; D019802:Succinic Acid; D005649:Fumarate Hydratase; C546174:IREB2 protein, human; D035942:Iron Regulatory Protein 2
keywords: FH; FOXM1; HLRCC; NRF2; ferritin; fumarate