Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Int J Mol Sci. 2020 Oct 31;21(21):8162. doi: 10.3390/ijms21218162.
Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel-Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.
氧平衡调节是调节生理氧变化的最基本的细胞过程，其异常导致包括癌症在内的各种人类疾病。缺氧与癌症的发展密切相关，缺氧/氧感应信号在调节癌症进展中起着关键作用。缺氧/氧感应信号的关键分子包括转录调节剂缺氧诱导因子（HIF），它广泛控制氧反应基因，2-氧戊二酸（2-OG）依赖性双氧酶的核心成员，如脯氨酰羟化酶（PHD 或 EglN），以及用于 HIF 降解的 E3 泛素连接酶组件称为 von Hippel-Lindau（编码蛋白 pVHL）。在这篇综述中，我们总结了关于经典缺氧信号、HIF 转录因子和 pVHL 的最新知识。此外，还专门回顾了 2-OG 依赖性酶（如 DNA/RNA 修饰酶、JmjC 结构域含有酶和脯氨酰羟化酶）在癌症进展中的基因调控中的作用。我们还讨论了针对癌症中缺氧和氧感应途径的治疗进展。
