Chen Hsiao-Fan, Wu Kou-Juey
Research Center for Tumor Medical Science and Graduate Inst. of Cancer Biology, China Medical University, 404, Taichung, Taiwan.
Biomedicine (Taipei). 2016 Mar;6(1):1. doi: 10.7603/s40681-016-0001-9. Epub 2016 Feb 10.
Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation with inadequate supply of oxygen. Tumor hypoxia is strongly associated with tumor propagation, malignant progression, and resistance to therapy. Aberrant epigenetic regulation plays a crucial role in the process of hypoxia-driven malignant progression. Convert of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5hmC and TET proteins was altered in various types of cancers. There is a strong correlation between loss of 5hmC and cancer development but research to date indicates that loss of TET activity is associated with the cancer phenotype but it is not clear whether TET proteins function as tumor suppressors or oncogenes. While loss of TET1 and TET2 expression is associated with solid cancers, implying a tumor suppressor role, TET1 exhibits a clear oncogenic role in the context of genomic rearrangements such as in MLL-fusion rearranged leukemia. Interestingly, hypoxia increases global 5hmC levels and upregulates TET1 expression in a HIF1α-dependent manner. Recently, hypoxia-induced TET1 has been demonstrated to play another important role for regulating hypoxia-responsive gene expression and epithelial-mesenchymal transition (EMT) by serving as a transcription co-activator. Furthermore, hypoxia-induced TET1 also regulates glucose metabolism and hypoxia-induced EMT through enhancing the expression of insulin induced gene 1 (INSIG1). The roles and mechanisms of action of 5hmC and TET proteins in ES cell biology and during embryonic development, as well as in cancer biology, will be the main focus in this review.
肿瘤中的缺氧主要是微循环在结构和功能上受到干扰、氧气供应不足所导致的病理生理后果。肿瘤缺氧与肿瘤增殖、恶性进展及治疗抵抗密切相关。异常的表观遗传调控在缺氧驱动的恶性进展过程中起关键作用。由十一-易位（TET）家族酶将5-甲基胞嘧啶（5mC）转化为5-羟甲基胞嘧啶（5hmC）在胚胎干细胞、发育、衰老及疾病过程中发挥重要生物学功能。最近的报道显示，5hmC水平和TET蛋白在多种类型癌症中发生改变。5hmC缺失与癌症发展之间存在很强的相关性，但迄今为止的研究表明，TET活性缺失与癌症表型相关，但尚不清楚TET蛋白是发挥肿瘤抑制因子还是癌基因的作用。虽然TET1和TET2表达缺失与实体癌相关，暗示其具有肿瘤抑制作用，但在基因组重排的情况下，如在MLL融合重排白血病中，TET1表现出明确的致癌作用。有趣的是，缺氧以HIF1α依赖的方式增加整体5hmC水平并上调TET1表达。最近，缺氧诱导的TET1已被证明通过作为转录共激活因子在调节缺氧反应基因表达和上皮-间质转化（EMT）中发挥另一个重要作用。此外，缺氧诱导的TET1还通过增强胰岛素诱导基因1（INSIG1）的表达来调节葡萄糖代谢和缺氧诱导的EMT。5hmC和TET蛋白在胚胎干细胞生物学、胚胎发育过程以及癌症生物学中的作用和作用机制将是本综述的主要重点。
