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

被引：117

作者：

Rodriguez-Bravo, Veronica ^{[1
,2
,3
]}

Pippa, Raffaella ^{[1
,2
,3
]}

Song, Won-Min ^{[4
,5
]}

Carceles-Cordon, Marc ^{[3
]}

Dominguez-Andres, Ana ^{[1
,2
,3
]}

Fujiwara, Naoto ^{[5
]}

Woo, Jungreem ^{[1
,2
,3
]}

Koh, Anna P. ^{[5
]}

Ertel, Adam ^{[1
]}

Lokareddy, Ravi K. ^{[6
]}

Cuesta-Dominguez, Alvaro ^{[7
,8
]}

Kim, Rosa S. ^{[5
]}

Rodriguez-Fernandez, Irene ^{[3
]}

Li, Peiyao ^{[1
,2
]}

Gordon, Ronald ^{[3
]}

Hirschfield, Hadassa ^{[5
]}

Prats, Josep M. ^{[9
]}

Reddy, E. Premkumar ^{[7
]}

Fatatis, Alessandro ^{[10
]}

Petrylak, Daniel P. ^{[11
]}

Gomella, Leonard ^{[12
]}

Kelly, W. Kevin ^{[1
,2
,12
]}

Lowe, Scott W. ^{[13
]}

Knudsen, Karen E. ^{[1
,2
,12
]}

Galsky, Matthew D. ^{[14
]}

Cingolani, Gino ^{[6
]}

Lujambio, Amaia ^{[7
,8
]}

Hoshida, Yujin ^{[1
,2
,3
]}

Domingo-Domenech, Josep ^{[1
,2
,3
]}

机构：

[1] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Canc Biol Dept, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Med Oncol Dept, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[3] Icahn Sch Med Mt Sinai, Pathol Dept, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Genet & Genom Sci Dept, New York, NY 10029 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Liver Tumor Translat Res Program, Dallas, TX 75390 USA

[6] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[7] Icahn Sch Med Mt Sinai, Oncol Sci Dept, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Med Dept, Div Liver Dis, New York, NY 10029 USA

[9] Hosp Calella, Urol Dept, Barcelona 08370, Spain

[10] Drexler Univ, Pharmacol & Physiol Dept, Philadelphia, PA 19104 USA

[11] Yale Sch Med, Med Oncol Dept, Yale Comprehens Canc Ctr, New Haven, CT 06520 USA

[12] Thomas Jefferson Univ, Urol Dept, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[13] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[14] Icahn Sch Med Mt Sinai, Med Oncol Dept, New York, NY 10029 USA

来源：

CELL | 2018年 / 174卷 / 05期

关键词：

CELL-CYCLE; INCREASED SURVIVAL; COMPLEX; DOCETAXEL; RECEPTOR; PROTEIN; MITOXANTRONE; PREDNISONE; PATHWAY; POM121;

D O I：

10.1016/j.cell.2018.07.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1200 / +

页数：36

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