Fumarate mediates a chronic proliferative signal in fumarate hydratase-inactivated cancer cells by increasing transcription and translation of ferritin genes

Michael John Kerins, Ajay Amar Vashisht, Benjamin Xi Tong Liang, Spencer Jordan Duckworth, Brandon John Praslicka, James Akira Wohlschlegel, Aikseng Ooi

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 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.

Original languageEnglish (US)
Article numbere00079-17
JournalMolecular and Cellular Biology
Volume37
Issue number11
DOIs
StatePublished - Jun 1 2017

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Fumarate Hydratase
Fumarates
Ferritins
Genes
Neoplasms
Citric Acid Cycle
Iron Regulatory Protein 2
Transcription Factors
Hereditary Neoplastic Syndromes
Germ-Line Mutation
Protein Biosynthesis
Growth
Cysteine
Iron
Enzymes

Keywords

  • Ferritin
  • FH
  • FOXM1
  • fumarate
  • HLRCC
  • NRF2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Fumarate mediates a chronic proliferative signal in fumarate hydratase-inactivated cancer cells by increasing transcription and translation of ferritin genes. / Kerins, Michael John; Vashisht, Ajay Amar; Liang, Benjamin Xi Tong; Duckworth, Spencer Jordan; Praslicka, Brandon John; Wohlschlegel, James Akira; Ooi, Aikseng.

In: Molecular and Cellular Biology, Vol. 37, No. 11, e00079-17, 01.06.2017.

Research output: Contribution to journalArticle

Kerins, Michael John ; Vashisht, Ajay Amar ; Liang, Benjamin Xi Tong ; Duckworth, Spencer Jordan ; Praslicka, Brandon John ; Wohlschlegel, James Akira ; Ooi, Aikseng. / Fumarate mediates a chronic proliferative signal in fumarate hydratase-inactivated cancer cells by increasing transcription and translation of ferritin genes. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 11.
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