Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
Oncogene. 2010 Oct 28;29(43):5818-27. doi: 10.1038/onc.2010.317. Epub 2010 Aug 9.
The helix-loop-helix inhibitor of differentiation and DNA binding (Id1) is well known as an oncogene in various tumors. Although it has been reported that Id1 promotes several oncogenic processes, it is still unclear whether Id1 functions through epigenetic transcriptional regulation. In this study, we examined the effect of Id1 on polycomb group (PcG) proteins, which are crucial epigenetic gene silencers, and found that Id1 regulated the expression of Mel-18 and Bmi-1, both of which belong to polycomb repressive complex 1. We also confirmed that Id1 induced Mel-18 downregulation, which was mediated by the Akt pathway, and consequently upregulated the transcription of its target gene, c-Myc. Using a promoter-reporter, we demonstrated that Id1 regulated Bmi-1 transcription through c-Myc binding to its E-box in the promoter. Finally, we examined the activity of E3 ligase RING1b, whose catalytic activity is increased by binding with the RING finger protein Bmi-1, and found that Id1 overexpression enhanced RING1b E3 ligase activity leading to accumulation of H2A ubiquitination and ubiquitin/proteasome-mediated degradation of geminin. Taken together, our study provided a novel link between Id1 and PcG proteins and suggested that Id1 may contribute to tumor development through PcG-mediated epigenetic regulation.
螺旋-环-螺旋结构域抑制因子分化和 DNA 结合蛋白（Id1）作为一种癌基因在多种肿瘤中被广泛研究。虽然已经报道 Id1 促进了几种致癌过程，但它是否通过表观遗传转录调控发挥作用仍不清楚。在本研究中，我们研究了 Id1 对多梳抑制复合物（PcG）蛋白的影响，PcG 蛋白是至关重要的表观遗传基因沉默因子，发现 Id1 调节了 Mel-18 和 Bmi-1 的表达，这两者都属于多梳抑制复合物 1。我们还证实，Id1 通过 Akt 通路诱导 Mel-18 的下调，从而上调其靶基因 c-Myc 的转录。通过启动子报告基因实验，我们证明 Id1 通过 c-Myc 与启动子中 E-box 的结合来调节 Bmi-1 的转录。最后，我们检测了 E3 连接酶 RING1b 的活性，其催化活性通过与 RING 指蛋白 Bmi-1 的结合而增加，发现 Id1 过表达增强了 RING1b E3 连接酶的活性，导致 H2A 泛素化的积累和泛素/蛋白酶体介导的 geminin 的降解。总之，我们的研究提供了 Id1 与 PcG 蛋白之间的新联系，并表明 Id1 可能通过 PcG 介导的表观遗传调控促进肿瘤的发展。
