2-Oxoglutarate-dependent dioxygenases in cancer.

Abstract

2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.

• Authors: Julie-Aurore Losman, Peppi Koivunen, William G Kaelin Jr
• Journal: Nature reviews. Cancer (Nat Rev Cancer) Vol. 20 Issue 12 Pg. 710-726 (12 2020) ISSN: 1474-1768 [Electronic] England
• PMID: 33087883 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ketoglutaric Acids
• Reactive Oxygen Species
• Dioxygenases
• EGLN1 protein, human
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Cell Hypoxia
• Citric Acid Cycle
• DNA Damage
• Dioxygenases (physiology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Hypoxia-Inducible Factor-Proline Dioxygenases (physiology)
• Ketoglutaric Acids (metabolism)
• Neoplasms (drug therapy, etiology, metabolism)
• Reactive Oxygen Species (metabolism)