A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer

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 () and Ronald M. Evans ()
Additional contact information
Corina E. Antal: Salk Institute for Biological Studies
Tae Gyu Oh: Salk Institute for Biological Studies
Stefan Aigner: University of California San Diego
En-Ching Luo: University of California San Diego
Brian A. Yee: University of California San Diego
Tania Campos: The Francis Crick Institute
Hervé Tiriac: University of California San Diego
Katherine L. Rothamel: University of California San Diego
Zhang Cheng: University of California San Diego
Henry Jiao: University of California San Diego
Allen Wang: University of California San Diego
Nasun Hah: Salk Institute for Biological Studies
Elizabeth Lenkiewicz: Mayo Clinic in Arizona
Jan C. Lumibao: Salk Institute for Biological Studies
Morgan L. Truitt: Salk Institute for Biological Studies
Gabriela Estepa: Salk Institute for Biological Studies
Ester Banayo: Salk Institute for Biological Studies
Senada Bashi: Salk Institute for Biological Studies
Edgar Esparza: University of California San Diego
Ruben M. Munoz: Translational Genomics Research Institute
Jolene K. Diedrich: Salk Institute for Biological Studies
Nicole M. Sodir: The Francis Crick Institute
Jasmine R. Mueller: University of California San Diego
Cory R. Fraser: HonorHealth Research Institute
Erkut Borazanci: Translational Genomics Research Institute
David Propper: Queen Mary University of London, Charterhouse Square
Daniel D. Von Hoff: Translational Genomics Research Institute
Christopher Liddle: University of Sydney, Westmead Hospital
Ruth T. Yu: Salk Institute for Biological Studies
Annette R. Atkins: Salk Institute for Biological Studies
Haiyong Han: Translational Genomics Research Institute
Andrew M. Lowy: The Francis Crick Institute
Michael T. Barrett: Translational Genomics Research Institute
Dannielle D. Engle: Salk Institute for Biological Studies
Gerard I. Evan: The Francis Crick Institute
Gene W. Yeo: University of California San Diego
Michael Downes: Salk Institute for Biological Studies
Ronald M. Evans: Salk Institute for Biological Studies

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40798-6

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