Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import Journal Article

Authors: Rodriguez-Bravo, V.; Pippa, R.; Song, W. M.; Carceles-Cordon, M.; Dominguez-Andres, A.; Fujiwara, N.; Woo, J.; Koh, A. P.; Ertel, A.; Lokareddy, R. K.; Cuesta-Dominguez, A.; Kim, R. S.; Rodriguez-Fernandez, I.; Li, P.; Gordon, R.; Hirschfield, H.; Prats, J. M.; Reddy, E. P.; Fatatis, A.; Petrylak, D. P.; Gomella, L.; Kelly, W. K.; Lowe, S. W.; Knudsen, K. E.; Galsky, M. D.; Cingolani, G.; Lujambio, A.; Hoshida, Y.; Domingo-Domenech, J.
Article Title: Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import
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.
Keywords: chemotherapy; protein; docetaxel; androgen receptor; pathway; complex; cell-cycle; gene-regulation; increased survival; nucleoporin pom121
Journal Title: Cell
Volume: 174
Issue: 5
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2018-08-23
Start Page: 1200
End Page: 1215.e20
Language: English
ACCESSION: WOS:000442529100016
DOI: 10.1016/j.cell.2018.07.015
PMCID: PMC6150493
PUBMED: 30100187
Notes: Article -- Source: Wos
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  1. Scott W Lowe
    144 Lowe