Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes
AuthorKerins, Michael John
Vashisht, Ajay Amar
Liang, Benjamin Xi-Tong
Duckworth, Spencer Jordan
Praslicka, Brandon John
Wohlschlegel, James Akira
AffiliationUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicol
MetadataShow full item record
PublisherAMER SOC MICROBIOLOGY
CitationFumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes 2017, 37 (11):e00079-17 Molecular and Cellular Biology
JournalMolecular and Cellular Biology
RightsCopyright © 2017 American Society for Microbiology.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractGerm 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 biallelic FH inactivation 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 how FH inactivation can endow cells with a growth advantage.
Note6 month embargo; published online 13 March 2017.
VersionFinal published version
SponsorsNational Science Foundation Graduate Research Fellowship Program [DGE-1143953]; University of Arizona College of Pharmacy; University of Arizona Health Sciences grant