دورية أكاديمية
أعرض في EDS

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.

التفاصيل البيبلوغرافية
العنوان: PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
المؤلفون: Giuliani V; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. VGiuliani@mdanderson.org., Miller MA; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Liu CY; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hartono SR; Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, CA, USA., Class CA; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Pharmaceutical Sciences, Butler University, Indianapolis, IN, USA., Bristow CA; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Suzuki E; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sanz LA; Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, CA, USA., Gao G; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gay JP; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Feng N; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Rose JL; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tomihara H; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Surgery, Kindai University Nara Hospital, Nara, JP, USA., Daniele JR; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Peoples MD; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bardenhagen JP; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Geck Do MK; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chang QE; ORBIT, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Vangamudi B; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Exo Therapeutics, Cambridge, MA, USA., Vellano C; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ying H; Department of Cellular and Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Deem AK; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Do KA; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Genovese G; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Marszalek JR; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kovacs JJ; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kim M; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Fleming JB; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Division of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Guccione E; Department of Oncological Sciences and Pharmacological Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA., Viale A; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Maitra A; Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Emilia Di Francesco M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yap TA; Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Jones P; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Draetta G; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Carugo A; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chedin F; Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, CA, USA., Heffernan TP; Traction, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. TPHeffernan@mdanderson.org.
المصدر: Nature communications [Nat Commun] 2021 Jul 30; Vol. 12 (1), pp. 4626. Date of Electronic Publication: 2021 Jul 30.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: DNA Damage*, Carcinoma, Pancreatic Ductal/*genetics , Pancreatic Neoplasms/*genetics , Protein-Arginine N-Methyltransferases/*genetics , RNA/*genetics , Repressor Proteins/*genetics, Animals ; Biocatalysis/drug effects ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/prevention & control ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/prevention & control ; Protein-Arginine N-Methyltransferases/metabolism ; RNA/metabolism ; RNA Interference ; Repressor Proteins/metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays/methods ; Mice
مستخلص: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
(© 2021. The Author(s).)
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معلومات مُعتمدة: P30 CA016672 United States CA NCI NIH HHS; R01 GM120607 United States GM NIGMS NIH HHS; UL1 TR003167 United States TR NCATS NIH HHS
المشرفين على المادة: 0 (Enzyme Inhibitors)
0 (Repressor Proteins)
63231-63-0 (RNA)
EC 2.1.1.319 (PRMT1 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
تواريخ الأحداث: Date Created: 20210731 Date Completed: 20210817 Latest Revision: 20240226
رمز التحديث: 20240226
مُعرف محوري في PubMed: PMC8324870
DOI: 10.1038/s41467-021-24798-y
PMID: 34330913
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-021-24798-y