Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import.
Publication/Presentation Date
8-23-2018
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.
Volume
174
Issue
5
First Page
1200
Last Page
1215
ISSN
1097-4172
Published In/Presented At
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., … Domingo-Domenech, J. (2018). Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import. Cell, 174(5), 1200–1215.e20. https://doi.org/10.1016/j.cell.2018.07.015
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
30100187
Department(s)
Administration and Leadership
Document Type
Article