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

TitleRibosome biogenesis during cell cycle arrest fuels EMT in development and disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsPrakash V, Carson BB, Feenstra JM, Dass RA, Sekyrova P, Hoshino A, Petersen J, Guo Y, Parks MM, Kurylo CM, Batchelder JE, Haller K, Hashimoto A, Rundqivst H, Condeelis JS, C Allis D, Drygin D, M Nieto A, Andäng M, Percipalle P, Bergh J, Adameyko I, Farrants A-KÖstlund, Hartman J, Lyden DC, Pietras K, Blanchard SC, C Vincent T
JournalNat Commun
Date Published2019 05 08
KeywordsAnimals, Breast Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Movement, Cell Nucleolus, Chick Embryo, Chromosomal Proteins, Non-Histone, Disease Models, Animal, DNA, Ribosomal, Epithelial-Mesenchymal Transition, Female, G1 Phase Cell Cycle Checkpoints, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Ribosomes, RNA, Ribosomal

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 (ERα) 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.

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Alternate JournalNat Commun
PubMed ID31068593
PubMed Central IDPMC6506521
Grant ListR01 GM079238 / GM / NIGMS NIH HHS / United States

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