Journal article
Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import
Cell, v 174(5), pp 1200-1215
23 Aug 2018
PMID: 30100187
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
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•Nuclear pores display a distinct Nup composition during progression to lethal PC•Nup POM121 impacts on PC aggressiveness by enhancing importin β function•POM121 promotes nuclear import of key transcription factors driving PC•Targeting the POM121-importin β axis decreases the aggressiveness of PC tumors
POM121- and importin β-mediated nuclear import of a subset of oncogenic transcription factors promotes prostate cancer aggressiveness and reveals a pharmacologically targetable dependency.
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Details
- Title
- Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import
- Creators
- Veronica Rodriguez-Bravo - Kimmel Cancer CenterRaffaella Pippa - Kimmel Cancer CenterWon-Min Song - Icahn School of Medicine at Mount SinaiMarc Carceles-Cordon - Icahn School of Medicine at Mount SinaiAna Dominguez-Andres - Kimmel Cancer CenterNaoto Fujiwara - Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Jungreem Woo - Kimmel Cancer CenterAnna P. Koh - Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Adam Ertel - Sidney Kimmel Cancer CenterRavi K. Lokareddy - Thomas Jefferson UniversityAlvaro Cuesta-Dominguez - Icahn School of Medicine at Mount SinaiRosa S. Kim - Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Irene Rodriguez-Fernandez - Icahn School of Medicine at Mount SinaiPeiyao Li - Kimmel Cancer CenterRonald Gordon - Icahn School of Medicine at Mount SinaiHadassa Hirschfield - Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Josep M. Prats - Hospital Sant Jaume de CalellaE. Premkumar Reddy - Icahn School of Medicine at Mount SinaiAlessandro Fatatis - Drexel UniversityDaniel P. Petrylak - Yale Cancer CenterLeonard Gomella - Thomas Jefferson UniversityW. Kevin Kelly - Thomas Jefferson UniversityScott W. Lowe - Memorial Sloan Kettering Cancer CenterKaren E. Knudsen - Thomas Jefferson UniversityMatthew D. Galsky - Icahn School of Medicine at Mount SinaiGino Cingolani - Thomas Jefferson UniversityAmaia Lujambio - Icahn School of Medicine at Mount SinaiYujin Hoshida - Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.Josep Domingo-Domenech - Kimmel Cancer Center
- Publication Details
- Cell, v 174(5), pp 1200-1215
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000442529100016
- Scopus ID
- 2-s2.0-85053121228
- Other Identifier
- 991019168380604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology