A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer
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Published:2023-09-06
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Antal Corina E.ORCID, Oh Tae Gyu, Aigner Stefan, Luo En-Ching, Yee Brian A.ORCID, Campos Tania, Tiriac HervéORCID, Rothamel Katherine L., Cheng Zhang, Jiao Henry, Wang Allen, Hah NasunORCID, Lenkiewicz Elizabeth, Lumibao Jan C., Truitt Morgan L., Estepa Gabriela, Banayo Ester, Bashi Senada, Esparza Edgar, Munoz Ruben M., Diedrich Jolene K., Sodir Nicole M., Mueller Jasmine R., Fraser Cory R., Borazanci Erkut, Propper DavidORCID, Von Hoff Daniel D.ORCID, Liddle Christopher, Yu Ruth T.ORCID, Atkins Annette R., Han HaiyongORCID, Lowy Andrew M., Barrett Michael T.ORCID, Engle Dannielle D., Evan Gerard I.ORCID, Yeo Gene W., Downes Michael, Evans Ronald M.ORCID
Abstract
AbstractPancreatic 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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