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A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
Antal, Corina E; Oh, Tae Gyu; Aigner, Stefan; Luo, En-Ching; Yee, Brian A; Campos, Tania; Tiriac, Hervé; Rothamel, Katherine L; Cheng, Zhang; Jiao, Henry; Wang, Allen; Hah, Nasun; 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, David; Von Hoff, Daniel D; Liddle, Christopher; Yu, Ruth T; Atkins, Annette R; Han, Haiyong; Lowy, Andrew M; Barrett, Michael T; Engle, Dannielle D; Evan, Gerard I; Yeo, Gene W; Downes, Michael; Evans, Ronald M.
Affiliation
  • Antal CE; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Oh TG; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
  • Aigner S; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
  • Luo EC; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Yee BA; Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
  • Campos T; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • Tiriac H; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • Rothamel KL; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • Cheng Z; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
  • Jiao H; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
  • Wang A; Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA.
  • Hah N; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • Lenkiewicz E; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA.
  • Lumibao JC; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA.
  • Truitt ML; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA.
  • Estepa G; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Banayo E; Mayo Clinic in Arizona, Scottsdale, AZ, 85259, USA.
  • Bashi S; Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Esparza E; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Munoz RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Diedrich JK; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Sodir NM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Mueller JR; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
  • Fraser CR; Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA.
  • Borazanci E; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
  • Propper D; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
  • Von Hoff DD; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
  • Liddle C; Genentech, Department of Translational Oncology, 1 DNA Way, South San Francisco, CA, 94080, USA.
  • Yu RT; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • Atkins AR; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA.
  • Han H; Scottsdale Pathology Associates, Scottsdale, AZ, 85260, USA.
  • Lowy AM; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
  • Barrett MT; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA.
  • Engle DD; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, USA.
  • Evan GI; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
  • Yeo GW; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA.
  • Downes M; Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW, 2145, Australia.
  • Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
Nat Commun ; 14(1): 5195, 2023 09 06.
Article in En | MEDLINE | ID: mdl-37673892
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.
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Full text: 1 Database: MEDLINE Main subject: Pancreatic Neoplasms / Carcinoma, Pancreatic Ductal Limits: Animals Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Pancreatic Neoplasms / Carcinoma, Pancreatic Ductal Limits: Animals Language: En Year: 2023 Type: Article