Yang Ming, Su Huizhong, Soga Tomoyoshi, Kranc Kamil R, Pollard Patrick J
Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Institute for Advanced Biosciences, Keio University, Mizukami, Tsuruoka, Yamagata, Japan.
Hypoxia (Auckl). 2014 Aug 30;2:127-142. doi: 10.2147/HP.S47968. eCollection 2014.
The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner. -4-prolyl hydroxylation of HIFα under normal oxygen (O) availability enables its association with the von Hippel-Lindau (VHL) tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin-proteasome pathway. Due to the obligatory requirement of molecular O as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFα, which dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites) that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism.
缺氧诱导因子（HIF）脯氨酰羟化酶结构域酶（PHDs）通过以氧依赖的方式对其α亚基中两个保守脯氨酰残基进行翻译后羟化来调节HIF蛋白的稳定性。在正常氧（O）供应下，HIFα的-4-脯氨酰羟化使其与冯·希佩尔-林道（VHL）肿瘤抑制蛋白pVHL E3连接酶复合物结合，导致HIFα通过泛素-蛋白酶体途径降解。由于分子氧作为共底物的必需需求，PHDs的活性在缺氧条件下受到抑制，导致HIFα稳定，其与HIFβ二聚化，并与转录共激活因子CBP/p300一起激活其靶基因的转录。作为对缺氧适应性反应的关键分子调节因子，HIF在多种细胞过程中发挥重要作用，并且在各种癌症中均检测到其过表达。特别是HIF1α异构体对细胞代谢有强烈影响，最显著的是通过促进无氧代谢，同时抑制氧依赖的葡萄糖代谢。PHD酶似乎也具有不依赖HIF的功能，并且受到除氧以外的因素调节，例如代谢状态、氧化应激以及在某些类型癌症中观察到的内源性代谢物（肿瘤代谢物）异常水平。在本综述中，我们旨在总结目前对PHDs在癌症中的功能和调节的理解，重点是它们在代谢中的作用。
