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

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

Author information

1
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: veronica.rodriguez-bravo@jefferson.edu.
2
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Genetic and Genomic Sciences Department. Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
7
Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
8
Oncological Sciences Department. Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Liver Diseases, Medicine Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
10
Urology Department, Hospital de Calella, Barcelona 08370, Spain.
11
Oncological Sciences Department. Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12
Pharmacology and Physiology Department, Drexler University, Philadelphia, PA 19104, USA.
13
Medical Oncology Department, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.
14
Urology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
15
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Urology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
16
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
17
Medical Oncology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
18
Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; Pathology Department, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: josep.domingo-domenech@jefferson.edu.

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:

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

PMID:
30100187
PMCID:
PMC6150493
[Available on 2019-08-23]
DOI:
10.1016/j.cell.2018.07.015
[Indexed for MEDLINE]

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