Nature Communications (Sep 2023)
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,
- Ronald M. Evans
Affiliations
- Corina E. Antal
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Tae Gyu Oh
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Stefan Aigner
- Department of Cellular and Molecular Medicine, University of California San Diego
- En-Ching Luo
- Department of Cellular and Molecular Medicine, University of California San Diego
- Brian A. Yee
- Department of Cellular and Molecular Medicine, University of California San Diego
- Tania Campos
- The Francis Crick Institute
- Hervé Tiriac
- Moores Cancer Center, University of California San Diego
- Katherine L. Rothamel
- Department of Cellular and Molecular Medicine, University of California San Diego
- Zhang Cheng
- Center for Epigenomics, University of California San Diego
- Henry Jiao
- Center for Epigenomics, University of California San Diego
- Allen Wang
- Center for Epigenomics, University of California San Diego
- Nasun Hah
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Elizabeth Lenkiewicz
- Mayo Clinic in Arizona
- Jan C. Lumibao
- Regulatory Biology Laboratory, Salk Institute for Biological Studies
- Morgan L. Truitt
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Gabriela Estepa
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Ester Banayo
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Senada Bashi
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Edgar Esparza
- Moores Cancer Center, University of California San Diego
- Ruben M. Munoz
- Molecular Medicine Division, Translational Genomics Research Institute
- Jolene K. Diedrich
- Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies
- Nicole M. Sodir
- The Francis Crick Institute
- Jasmine R. Mueller
- Department of Cellular and Molecular Medicine, University of California San Diego
- Cory R. Fraser
- HonorHealth Research Institute
- Erkut Borazanci
- Molecular Medicine Division, Translational Genomics Research Institute
- David Propper
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square
- Daniel D. Von Hoff
- Molecular Medicine Division, Translational Genomics Research Institute
- Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital
- Ruth T. Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Annette R. Atkins
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Haiyong Han
- Molecular Medicine Division, Translational Genomics Research Institute
- Andrew M. Lowy
- The Francis Crick Institute
- Michael T. Barrett
- Molecular Medicine Division, Translational Genomics Research Institute
- Dannielle D. Engle
- Regulatory Biology Laboratory, Salk Institute for Biological Studies
- Gerard I. Evan
- The Francis Crick Institute
- Gene W. Yeo
- Department of Cellular and Molecular Medicine, University of California San Diego
- Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies
- Ronald M. Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies
- DOI
- https://doi.org/10.1038/s41467-023-40798-6
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
