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

Autor:	Antal CE; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA., Oh TG; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.; Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA., Aigner S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Luo EC; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Yee BA; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Campos T; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK., Tiriac H; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.; Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA., Rothamel KL; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Cheng Z; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA., Jiao H; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA., Wang A; Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA., Hah N; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Lenkiewicz E; Mayo Clinic in Arizona, Scottsdale, AZ, 85259, USA., Lumibao JC; Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Truitt ML; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Estepa G; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Banayo E; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Bashi S; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Esparza E; Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.; Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA., Munoz RM; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA., Diedrich JK; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Sodir NM; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.; Genentech, Department of Translational Oncology, 1 DNA Way, South San Francisco, CA, 94080, USA., Mueller JR; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA., Fraser CR; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA.; Scottsdale Pathology Associates, Scottsdale, AZ, 85260, USA., Borazanci E; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA., Propper D; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, USA., Von Hoff DD; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.; HonorHealth Research Institute, Scottsdale, AZ, 85258, USA., Liddle C; Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW, 2145, Australia., Yu RT; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Atkins AR; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Han H; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA., Lowy AM; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.; Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA., Barrett MT; Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA., Engle DD; Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA., Evan GI; The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK., Yeo GW; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.; Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, 92037, USA., Downes M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA. downes@salk.edu., Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA. evans@salk.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2023 Sep 06; Vol. 14 (1), pp. 5195. Date of Electronic Publication: 2023 Sep 06.
DOI:	10.1038/s41467-023-40798-6
Abstrakt:	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. (© 2023. Springer Nature Limited.)
Databáze:	MEDLINE
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