一个受超级增强子调控的RNA结合蛋白级联驱动胰腺癌的发展。
A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
发表日期：2023 Sep 06
作者：
Corina E Antal, Tae Gyu Oh, Stefan Aigner, En-Ching Luo, Brian A Yee, Tania Campos, Hervé Tiriac, Katherine L Rothamel, Zhang Cheng, Henry Jiao, Allen Wang, Nasun Hah, Elizabeth Lenkiewicz, Jan C Lumibao, Morgan L Truitt, Gabriela Estepa, Ester Banayo, Senada Bashi, Edgar Esparza, Ruben M Munoz, Jolene K Diedrich, Nicole M Sodir, Jasmine R Mueller, Cory R Fraser, Erkut Borazanci, David Propper, Daniel D Von Hoff, Christopher Liddle, Ruth T Yu, Annette R Atkins, Haiyong Han, Andrew M Lowy, Michael T Barrett, Dannielle D Engle, Gerard I Evan, Gene W Yeo, Michael Downes, Ronald M Evans
来源：
Epigenetics & Chromatin
摘要：
胰腺导管腺癌（PDAC）是一种需要新治疗选择的致命恶性肿瘤。本研究利用无偏倚的超增强子（SE）分析作为细胞特异性功能核心基因的标志，揭示了一种可药物靶向的SE介导的RNA结合蛋白（RBP）级联反应，通过增强mRNA翻译促进PDAC生长。这种级联反应是由与RBP异核核糖核蛋白F相关的SE所驱动的，该SE稳定了蛋白质精氨酸甲基转移酶1（PRMT1），进而控制了翻译介质泛素相关蛋白2样。这三个基因和调控的SE对于PDAC的生长至关重要，并且由Myc癌基因协调调节。与此一致，PRMT1抑制对Myc高表达的PDAC患者器官样体显示了RBP网络的调节的独特敏感性，并且显著减少了雄性小鼠的肿瘤生长。我们的研究突显了表观遗传调控与mRNA翻译之间的功能联系，并确定了组成PDAC意外治疗靶点的组分。© 2023. Springer Nature Limited.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.© 2023. Springer Nature Limited.