Abstract：
Our previous studies determined that elevating SOX2 in a wide range of tumor cells leads to a reversible state of tumor growth arrest. Efforts to understand how tumor cell growth is inhibited led to the discovery of a SOX2:MYC axis that is responsible for downregulating c-MYC (MYC) when SOX2 is elevated. Although we had determined that elevating SOX2 downregulates MYC transcription, the mechanism responsible was not determined. Given the challenges of targeting MYC clinically, we set out to identify how elevating SOX2 downregulates MYC transcription. In this study, we focused on the MYC promoter region and an upstream region of the MYC locus that contains a MYC super-enhancer encompassing five MYC enhancers and which is associated with several cancers. Here we report that BRD4 and p300 associate with each of the MYC enhancers in the upstream MYC super-enhancer as well as the MYC promoter region and that elevating SOX2 decreases the recruitment of BRD4 and p300 to these sites. Additionally, we determined that elevating SOX2 leads to increases in the association of SOX2 and H3K27me3 within the MYC super-enhancer and the promoter region of MYC. Importantly, we conclude that the increases in SOX2 within the MYC super-enhancer precipitate a cascade of events that culminates in the repression of MYC transcription. Together, our studies identify a novel molecular mechanism able to regulate MYC transcription in two distinctly different tumor types and provide new mechanistic insights into the molecular interrelationships between two master regulators, SOX2 and MYC, widely involved in multiple cancers.
摘要：
我们先前的研究确定，在广泛的肿瘤细胞中升高SOX2会导致肿瘤生长停滞的可逆状态。了解肿瘤细胞生长如何被抑制的努力导致SOX2：MYC轴的发现，当SOX2升高时，该轴负责下调c-MYC（MYC）。虽然我们已经确定提高SOX2下调MYC转录，责任机制尚未确定。鉴于临床上针对MYC的挑战，我们着手确定如何提高SOX2下调MYC转录。在这项研究中,我们关注MYC启动子区和MYC基因座的上游区域,该区域含有包含5个MYC增强子的MYC超增强子,并且与几种癌症相关.在这里，我们报告了BRD4和p300与上游MYC超增强子以及MYC启动子区域中的每个MYC增强子相关联，并且升高SOX2会减少BRD4和p300对这些位点的募集。此外,我们确定，升高SOX2会导致MYC超增强子和MYC启动子区域中SOX2和H3K27me3的关联增加。重要的是,我们得出的结论是，MYC超级增强子中SOX2的增加会导致一系列事件，最终导致MYC转录的抑制。一起,我们的研究确定了一种新的分子机制，能够在两种截然不同的肿瘤类型中调节MYC转录，并为两种主要调节因子之间的分子相互关系提供了新的机制见解。SOX2和MYC，广泛参与多种癌症。
