PDF(Pubmed)
Abstract：
Deregulation of ten-eleven Translocation protein 1 (TET1) is commonly reported to induce imbalances in gene expression and subsequently to colorectal cancer development (CRC). On the other hand, vitamin C (VitC) improves the prognosis of colorectal cancer by reprogramming the cancer epigenome and limiting chemotherapeutic drug resistance events. In this study, we aimed to characterize TET1-specific subcellular compartments and evaluate the effect of VitC on TET1 compartmentalization in colonic tumour cells. We demonstrated that TET1 is concentrated in coarse nuclear bodies (NB) and 5-hydroxymethylcytosine (5hmC) in foci in colorectal cancer cells (HCT116, Caco-2, and HT-29). To our knowledge, this is the first report of a novel intracellular localization profile of TET1 and its demethylation marker, 5hmC, in CRC cells. Interestingly, we found that TET1-NBs frequently interacted with Cajal bodies, but not with promyelocytic leukaemia (PML) bodies. In addition, we report that VitC treatment of HCT116 cells induces 5hmC foci biogenesis and triggers 5hmC marks to form active complexes with nuclear body components, including both Cajal and PML proteins. Our data highlight novel NB-concentrating TET1 in CRC cells and demonstrate that VitC modulates TET1-NBs\' interactions with other nuclear structures. These findings reveal novel TET1-dependent cellular functions and potentially provide new insights for CRC management.
摘要：
据报道，十11易位蛋白1（TET1）的失调通常会导致基因表达失衡，并随后导致结直肠癌（CRC）的发展。另一方面,维生素C（VitC）通过重编程癌症表观基因组和限制化疗药物耐药事件改善结直肠癌的预后。在这项研究中,我们旨在表征TET1特异性亚细胞区室，并评估VitC对结肠肿瘤细胞TET1区室化的影响。我们证明了TET1集中在结直肠癌细胞（HCT116，Caco-2和HT-29）病灶中的粗核体（NB）和5-羟甲基胞嘧啶（5hmC）中。据我们所知,这是TET1及其去甲基化标记的新型细胞内定位谱的首次报道，5hmC，在CRC细胞中。有趣的是,我们发现TET1-NB经常与Cajal身体相互作用，但不与早幼粒细胞白血病（PML）的身体。此外,我们报道，VitC处理HCT116细胞诱导5hmC灶生物发生，并触发5hmC标记与核体成分形成活性复合物，包括Cajal和PML蛋白。我们的数据突出了CRC细胞中新型的NB浓缩TET1，并证明了VitC调节TET1-NBs与其他核结构的相互作用。这些发现揭示了新的TET1依赖性细胞功能，并可能为CRC管理提供新的见解。
