核孔通过蛋白质的无规则区域捕获鳞状细胞癌细胞中的超级增强子。

Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells.

机构信息

Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Laboratory of molecular cell biology, School of Natural System, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

出版信息

Cell Chem Biol. 2024 Apr 18;31(4):792-804.e7. doi: 10.1016/j.chembiol.2023.10.005. Epub 2023 Nov 3.

DOI:10.1016/j.chembiol.2023.10.005

PMID:37924814

Abstract

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.

摘要

主转录因子如 TP63 建立超级增强子 (SEs) 以驱动癌细胞中的核心转录网络，但核内 SEs 的时空调节仍然未知。核孔复合物 (NPC) 可能将 SEs 固定在核孔上，在核孔处 RNA 输出速率最大。在这里，我们报告说 NPC 的组成部分 NUP153 将 SEs 锚定在 NPC 上，并通过最大化 mRNA 输出来增强 TP63 的表达。这种固定是通过 NUP153 的固有无序区域 (IDR) 与共激活因子 BRD4 之间的蛋白-蛋白相互作用介导的。NUP153 的沉默将 SEs 排除在核周之外，降低 TP63 的表达，损害细胞生长，并诱导鳞状细胞癌的表皮分化。总的来说，这项工作揭示了 NUP153 IDR 在 SE 定位调节中的关键作用，从而为在表观基因组和空间水平上的基因调控提供了新的认识。