SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth

Xianghui Zou, Yueming Zhu, Seong Hoon Park, Guoxiang Liu, Joseph O'Brien, Haiyan Jiang, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. IHC staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.

Original languageEnglish (US)
Pages (from-to)3990-3999
Number of pages10
JournalCancer Research
Volume77
Issue number15
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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