Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear Import

Veronica Rodriguez-Bravo, Raffaella Pippa, Won Min Song, Marc Carceles-Cordon, Ana Dominguez-Andres, Naoto Fujiwara, Jungreem Woo, Anna P. Koh, Adam Ertel, Ravi K. Lokareddy, Alvaro Cuesta-Dominguez, Rosa S. Kim, Irene Rodriguez-Fernandez, Peiyao Li, Ronald Gordon, Hadassa Hirschfield, Josep M. Prats, E. Premkumar Reddy, Alessandro Fatatis, Daniel P. PetrylakLeonard Gomella, W. Kevin Kelly, Scott W. Lowe, Karen E. Knudsen, Matthew D. Galsky, Gino Cingolani, Amaia Lujambio, Yujin Hoshida, Josep Domingo-Domenech

Research output: Contribution to journalArticle

23 Scopus citations

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. POM121- and importin β-mediated nuclear import of a subset of oncogenic transcription factors promotes prostate cancer aggressiveness and reveals a pharmacologically targetable dependency.

Original languageEnglish (US)
Pages (from-to)1200-1215.e20
JournalCell
Volume174
Issue number5
DOIs
StatePublished - Aug 23 2018

Keywords

  • E2F1
  • GATA2
  • MYC
  • POM121
  • androgen receptor
  • importin β
  • nuclear import
  • nuclear pore
  • nuclear transport
  • prostate cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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., ... 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