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

Cell. 2018 Aug 23;174(5):1200-1215.e20. doi: 10.1016/j.cell.2018.07.015. Epub 2018 Aug 9.


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: E2F1; GATA2; MYC; POM121; androgen receptor; importin β; nuclear import; nuclear pore; nuclear transport; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Carcinogenesis
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • E2F1 Transcription Factor / metabolism*
  • GATA2 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism*
  • Nuclear Envelope
  • Nuclear Pore / physiology*
  • Nuclear Pore Complex Proteins
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism*


  • E2F1 Transcription Factor
  • E2F1 protein, human
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • MYC protein, human
  • Membrane Glycoproteins
  • Nuclear Pore Complex Proteins
  • POM121 protein, human
  • Proto-Oncogene Proteins c-myc
  • TCF20 protein, human
  • Transcription Factors