Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Nat Rev Cancer. 2020 Dec;20(12):710-726. doi: 10.1038/s41568-020-00303-3. Epub 2020 Oct 21.
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.
2- 氧戊二酸依赖性双加氧酶（2OGDDs）是一个超家族的酶，在许多生物学过程中发挥着多样化的作用，包括调节缺氧诱导因子介导的对缺氧的适应、细胞外基质的形成、基因转录的表观遗传调控以及细胞代谢的重编程。2OGDDs 都需要氧气、还原铁和 2- 氧戊二酸（也称为α-酮戊二酸）才能发挥作用，尽管它们对每种辅助底物的亲和力不同，因此对特定辅助底物的消耗的敏感性也有很大差异。许多 2OGDDs 在癌症中反复失调。此外，癌症特异性代谢变化，如那些发生在编码琥珀酸脱氢酶、延胡索酸水合酶或异柠檬酸脱氢酶的基因突变之后的变化，可以使特定的 2OGDDs 失调。后一种观察结果表明，2OGDD 在癌症中的作用不仅限于那些在编码 2OGDD 超家族成员的基因中存在突变的癌症。本文综述了 2OGDD 在正常细胞中的调节以及这种调节在癌症中是如何被破坏的。
