Department of Laboratory Medicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, University of Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
Mol Oncol. 2022 Jul;16(13):2470-2495. doi: 10.1002/1878-0261.13195. Epub 2022 Mar 19.
FET fusion oncoproteins containing one of the FET (FUS, EWSR1, TAF15) family proteins juxtaposed to alternative transcription-factor partners are characteristic of more than 20 types of sarcoma and leukaemia. FET oncoproteins bind to the SWI/SNF chromatin remodelling complex, which exists in three subtypes: cBAF, PBAF and GBAF/ncBAF. We used comprehensive biochemical analysis to characterize the interactions between FET oncoproteins, SWI/SNF complexes and the transcriptional coactivator BRD4. Here, we report that FET oncoproteins bind all three main SWI/SNF subtypes cBAF, PBAF and GBAF, and that FET oncoproteins interact indirectly with BRD4 via their shared interaction partner SWI/SNF. Furthermore, chromatin immunoprecipitation sequencing and proteomic analysis showed that FET oncoproteins, SWI/SNF components and BRD4 co-localize on chromatin and interact with mediator and RNA Polymerase II. Our results provide a possible molecular mechanism for the FET-fusion-induced oncogenic transcriptional profiles and may lead to novel therapies targeting aberrant SWI/SNF complexes and/or BRD4 in FET-fusion-caused malignancies.
含有 FET（FUS、EWSR1、TAF15）家族蛋白之一的 FET 融合癌蛋白与其他转录因子伴侣并列，是 20 多种肉瘤和白血病的特征。FET 癌蛋白与 SWI/SNF 染色质重塑复合物结合，该复合物存在三种亚型：cBAF、PBAF 和 GBAF/ncBAF。我们使用全面的生化分析来表征 FET 癌蛋白、SWI/SNF 复合物和转录共激活因子 BRD4 之间的相互作用。在这里，我们报告 FET 癌蛋白结合三种主要的 SWI/SNF 亚型 cBAF、PBAF 和 GBAF，并且 FET 癌蛋白通过其共享的相互作用伙伴 SWI/SNF 与 BRD4 间接相互作用。此外，染色质免疫沉淀测序和蛋白质组学分析表明，FET 癌蛋白、SWI/SNF 成分和 BRD4 共定位于染色质上，并与中介体和 RNA 聚合酶 II 相互作用。我们的结果为 FET 融合诱导的致癌转录谱提供了一个可能的分子机制，并可能导致针对 FET 融合引起的恶性肿瘤中异常 SWI/SNF 复合物和/或 BRD4 的新疗法。
