Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

被引：165

作者：

Prakash, Varsha ^{[1
,2
]}

Carson, Brittany B. ^{[1
]}

Feenstra, Jennifer M. ^{[1
,2
]}

Dass, Randall A. ^{[3
]}

Sekyrova, Petra ^{[2
]}

Hoshino, Ayuko ^{[4
,5
]}

Petersen, Julian ^{[1
,6
]}

Guo, Yuan ^{[7
]}

Parks, Matthew M. ^{[3
,4
]}

Kurylo, Chad M. ^{[3
,4
]}

Batchelder, Jake E. ^{[3
,4
]}

Haller, Kristian ^{[8
]}

Hashimoto, Ayako ^{[4
,5
]}

Rundqivst, Helene ^{[9
]}

Condeelis, John S. ^{[10
,11
]}

Allis, C. David ^{[12
]}

Drygin, Denis ^{[13
]}

Nieto, M. Angela ^{[14
]}

Andang, Michael ^{[2
]}

Percipalle, Piergiorgio ^{[15
]}

Bergh, Jonas ^{[16
,17
]}

Adameyko, Igor ^{[1
,6
]}

Farrants, Ann-Kristin Ostlund ^{[7
]}

Hartman, Johan ^{[16
,17
]}

Lyden, David ^{[4
,5
]}

Pietras, Kristian ^{[8
]}

Blanchard, Scott C. ^{[3
,4
,18
]}

Vincent, C. Theresa ^{[1
,2
,3
,4
]}

机构：

[1] Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden

[2] Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden

[3] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA

[4] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA

[5] Weill Cornell Med Coll, Dept Pediat & Cell & Dev Biol, New York, NY 10065 USA

[6] Med Univ Vienna, Dept Brain Res, A-1090 Vienna, Austria

[7] Stockholm Univ, Dept Mol Biosci, Wenner Gren Inst, S-10691 Stockholm, Sweden

[8] Lund Univ, Dept Lab Med, Ctr Mol Pathol, SE-22381 Lund, Sweden

[9] Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden

[10] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA

[11] Montefiore Med Ctr, Dept Pathol, Bronx, NY 10461 USA

[12] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA

[13] Pimera Inc, 3210 Merryfield Row, San Diego, CA 92121 USA

[14] UMH, CSIC, Inst Neurociencias, Alicante 03550, Spain

[15] New York Univ Abu Dhabi, Div Sci, Biol Program, Abu Dhabi 129188, U Arab Emirates

[16] Karolinska Inst, Dept Pathol & Oncol, S-17176 Solna, Sweden

[17] Univ Hosp, S-17176 Solna, Sweden

[18] Weill Cornell Med, Triinst Training Program Chem Biol, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

RNA-POLYMERASE-I; TGF-BETA; BREAST-CANCER; MESENCHYMAL TRANSITION; EMERGING TARGET; TRANSCRIPTION; ACTIVATION; COMPLEX; PROTEIN; STRESS;

D O I：

10.1038/s41467-019-10100-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

引用

页数：16

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