title: The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling.
abstract: Inactivating mutations of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH) have been linked to an aggressive variant of hereditary kidney cancer (hereditary leiomyomatosis and renal cell cancer). These tumors accumulate markedly elevated levels of fumarate. Fumarate is among a growing list of oncometabolites identified in cancers with mutations of genes involved in intermediary metabolism. FH-deficient tumors are notable for their pronounced accumulation of the transcription factor hypoxia inducible factor-1α (HIF-1α) and aggressive behavior. To date, HIF-1α accumulation in hereditary leiomyomatosis and renal cell cancer tumors is thought to result from fumarate-dependent inhibition of prolyl hydroxylases and subsequent evasion from von Hippel-Lindau-dependent degradation. Here, we demonstrate a novel mechanism by which fumarate promotes HIF-1α mRNA and protein accumulation independent of the von Hippel-Lindau pathway. Here we demonstrate that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank binding kinase 1 (TBK1). Consistent with these data, inhibition of the TBK1/p65 axis blocks HIF-1α accumulation in cellular models of FH loss and markedly reduces cell invasion of FH-deficient RCC cancer cells. Collectively, our data demonstrate a novel mechanism by which pseudohypoxia is promoted in FH-deficient tumors and identifies TBK1 as a novel putative therapeutic target for the treatment of aggressive fumarate-driven tumors.
authors.affiliation: From the Departments of Medicine and.
authors.forename: Karthigayan
authors.initials: K
authors.lastname: Shanmugasundaram
authors.affiliation: From the Departments of Medicine and.
authors.forename: Bijaya
authors.initials: B
authors.lastname: Nayak
authors.affiliation: the Department of Urology, University of Alabama, Birmingham, Alabama 35294, and.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Shim
authors.affiliation: Molecular Medicine, University of Texas Health Sciences Center, San Antonio, Texas 78229.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.affiliation: From the Departments of Medicine and the South Texas Veterans Health Care System, Audie L. Murphy Memorial Hospital Division, San Antonio, Texas 78229 block@uthscsa.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Block
authors.affiliation: the Department of Urology, University of Alabama, Birmingham, Alabama 35294, and sudarshan@uab.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sudarshan
mesh_terms: D001483:Base Sequence; D015687:Cell Hypoxia; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D005650:Fumarates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; C032005:fumaric acid
keywords: Cancer Biology; Cell Metabolism; Hypoxia-inducible Factor (HIF); NF-κB (NF-KB); Small; Small Molecule