Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.

Koivunen, Peppi

Lee, Sungwoo

Duncan, Christopher G

Lopez, Giselle

Lu, Gang

Ramkissoon, Shakti

Losman, Julie A

Joensuu, Päivi

Bergmann, Ulrich

Gross, Stefan

Travins, Jeremy

Weiss, Samuel

Looper, Ryan

Ligon, Keith L

Verhaak, Roel GW

Yan, Hai

Kaelin, William G

2019-01-02T22:34:06Z

2019-01-02T22:34:06Z

2012-02-15

2019-01-02T22:34:04Z

The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.

nature10898

0028-0836

1476-4687

https://hdl.handle.net/10161/17847

eng

Springer Science and Business Media LLC

Nature

10.1038/nature10898

Astrocytes

Cell Line

Cell Line, Tumor

Humans

Glioma

Cell Transformation, Neoplastic

Glutarates

Isocitrate Dehydrogenase

Dioxygenases

Procollagen-Proline Dioxygenase

Nuclear Proteins

Cell Proliferation

Enzyme Activation

Oncogenes

Hypoxia-Inducible Factor 1

Hypoxia-Inducible Factor-Proline Dioxygenases

Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.

Journal article

Lopez, Giselle|0000-0001-5435-6668

Yan, Hai|0000-0001-9509-8431

484

488

7390

School of Medicine

Duke

Duke Cancer Institute

Institutes and Centers

Pharmacology & Cancer Biology

Basic Science Departments

Pathology

Clinical Science Departments

Published

483