Fumarate hydratase inactivation in renal tumors: HIF1α, NRF2 and "cryptic targets" of transcription factors

Aikseng Ooi, Kyle A. Furge

Research output: Contribution to journalReview article

23 Scopus citations

Abstract

Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-lik e 2 (NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors. One such cryptic target is heme oxygenase I (HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).

Original languageEnglish (US)
Pages (from-to)413-420
Number of pages8
JournalChinese Journal of Cancer
Volume31
Issue number9
DOIs
StatePublished - Sep 28 2012

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Keywords

  • Fumarate hydratase
  • HIF1A
  • HLRCC
  • NRF2
  • Renal cancer

ASJC Scopus subject areas

  • Oncology

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