Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1α stabilization by glucose-dependent generation of reactive oxygen species

Sunil Sudarshan, Carole Sourbier, Hye Sik Kong, Karen Block, Vladimir A. Valera Romero, Youfeng Yang, Cynthia Galindo, Mehdi Mollapour, Bradley Scroggins, Norman Goode, Min Jung Lee, Campbell W. Gourlay, Jane Trepel, W. Marston Linehan, Len Neckers

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive - the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension - is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the α subunit of the hypoxia-inducible transcription factor (HIF-1α). Under normoxic conditions, proline hydroxylation of HIF-1α permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1α stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1α stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.

Original languageEnglish (US)
Pages (from-to)4080-4090
Number of pages11
JournalMolecular and cellular biology
Volume29
Issue number15
DOIs
StatePublished - Aug 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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