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Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import.
- Source :
-
Cell [Cell] 2018 Aug 23; Vol. 174 (5), pp. 1200-1215.e20. Date of Electronic Publication: 2018 Aug 09. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Active Transport, Cell Nucleus
Carcinogenesis
Cell Nucleus metabolism
Cell Proliferation
GATA2 Transcription Factor metabolism
Gene Expression Regulation, Neoplastic
Humans
Male
Nuclear Envelope
Nuclear Pore Complex Proteins
Signal Transduction
E2F1 Transcription Factor metabolism
Membrane Glycoproteins metabolism
Nuclear Pore physiology
Prostatic Neoplasms metabolism
Proto-Oncogene Proteins c-myc metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 174
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 30100187
- Full Text :
- https://doi.org/10.1016/j.cell.2018.07.015