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

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

Cell (2018-08-14)
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 Petrylak, Leonard Gomella, W Kevin Kelly, Scott W Lowe, Karen E Knudsen, Matthew D Galsky, Gino Cingolani, Amaia Lujambio, Yujin Hoshida, Josep Domingo-Domenech
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-α-Tubulin Mouse mAb (DM1A), liquid, clone DM1A, Calbiochem®
Sigma-Aldrich
Anti-GATA2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution