Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import
| Autor: | Irene Rodriguez-Fernandez, Daniel P. Petrylak, Leonard G. Gomella, J. M. Prats, Ana Dominguez-Andres, Alessandro Fatatis, Naoto Fujiwara, Hadassa Hirschfield, Raffaella Pippa, Josep Domingo-Domenech, Jungreem Woo, Gino Cingolani, Amaia Lujambio, Adam Ertel, Yujin Hoshida, E. Premkumar Reddy, Scott W. Lowe, Ravi K. Lokareddy, Won-Min Song, Ronald E. Gordon, Matthew D. Galsky, Marc Carceles-Cordon, Peiyao Li, Alvaro Cuesta-Dominguez, Anna P. Koh, Rosa S. Kim, Karen E. Knudsen, W. Kevin Kelly, Veronica Rodriguez-Bravo |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Carcinogenesis Nuclear Envelope Active Transport Cell Nucleus Biology General Biochemistry Genetics and Molecular Biology Proto-Oncogene Proteins c-myc Transcriptome 03 medical and health sciences Prostate cancer 0302 clinical medicine medicine Humans E2F1 Nuclear pore Transcription factor Cell Proliferation Cell Nucleus Membrane Glycoproteins Prostatic Neoplasms medicine.disease GATA2 Transcription Factor Gene Expression Regulation Neoplastic Nuclear Pore Complex Proteins 030104 developmental biology 030220 oncology & carcinogenesis Nuclear Pore Cancer research Nucleoporin Nuclear transport E2F1 Transcription Factor Signal Transduction Transcription Factors Genetic screen |
| Zdroj: | Cell. 174:1200-1215.e20 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2018.07.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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