s41467-023-40798-6.pdf (2.89 MB)
A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
journal contributionposted on 2023-09-11, 11:26 authored by 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
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.