Rare insights into cancer biology

J. Adam, M. Yang, T. Soga, P. J. Pollard

研究成果: Review article査読

63 被引用数 (Scopus)

抄録

Cancer-associated mutations have been identified in the metabolic genes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent dioxygenases, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases, JmjC domain-containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways and inhibition of histone and DNA demethylation. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology associated with dysregulated metabolism and represents a useful paradigm for cancer research.

本文言語English
ページ(範囲)2547-2556
ページ数10
ジャーナルOncogene
33
20
DOI
出版ステータスPublished - 2014 5月 15

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 癌研究

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