Research Papers:

CPEB1 orchestrates a fine-tuning of miR-145-5p tumor-suppressive activity on TWIST1 translation in prostate cancer cells

Fatemeh Rajabi, Win-Yan Liu-Bordes, Marina Pinskaya, Foretek Dominika, Gueorgui Kratassiouk, Guillaume Pinna, Simona Nanni, Antonella Farsetti, Christian Gespach, Arturo Londoño-Vallejo _ and Irina Groisman _

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Oncotarget. 2020; 11:4155-4168. https://doi.org/10.18632/oncotarget.27806

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Fatemeh Rajabi1, Win-Yan Liu-Bordes1, Marina Pinskaya2, Foretek Dominika2, Gueorgui Kratassiouk3, Guillaume Pinna3, Simona Nanni5,6, Antonella Farsetti4, Christian Gespach7, Arturo Londoño-Vallejo1 and Irina Groisman1

1 Telomeres and Cancer Laboratory, CNRS, Sorbonne Université, Université PSL, Institut Curie, Paris, France

2 Non-Coding RNA, Epigenetic and Genome Fluidity, Sorbonne Université, Université PSL, Institut Curie, Paris, France

3 Plateforme ARN Interférence, Service de Biologie Intégrative et de Génétique Moléculaire (SBIGeM), Gif-sur-Yvette, France

4 Istituto di Biologia Cellulare e Neurobiologia, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy

5 Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, Rome, Italy

6 Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy

7 Sorbonne Université, Inserm U938, Team TGFβ Signaling in Cellular Plasticity and Cancer, Centre de Recherche Saint-Antoine, Paris, France

Correspondence to:

Arturo Londoño-Vallejo,email: Jose-Arturo.Londono-Vallejo@curie.fr
Irina Groisman,email: irina.groisman@gmail.com

Keywords: miR-145-5p; TWIST1; CPEB1; EMT; prostate cancer

Received: August 31, 2020     Accepted: October 27, 2020     Published: November 10, 2020

Copyright: © 2020 Rajabi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


TWIST1 is a basic helix-loop-helix transcription factor, and one of the master Epithelial-to-Mesenchymal Transition (EMT) regulators. We show that tumor suppressor miR-145-5p controls TWIST1 expression in an immortalized prostate epithelial cell line and in a tumorigenic prostate cancer-derived cell line. Indeed, shRNA-mediated miR-145-5p silencing enhanced TWIST1 expression and induced EMT-associated malignant properties in these cells. However, we discovered that the translational inhibitory effect of miR-145-5p on TWIST1 is lost in 22Rv1, another prostate cancer cell line that intrinsically expresses high levels of the CPEB1 cytoplasmic polyadenylation element binding protein. This translational regulator typically reduces TWIST1 translation efficiency by shortening the TWIST1 mRNA polyA tail. However, our results indicate that the presence of CPEB1 also interferes with the binding of miR-145-5p to the TWIST1 mRNA 3′UTR. Mechanistically, CPEB1 binding to its first cognate site either directly hampers the access to the miR-145-5p response element or redirects the cleavage/polyadenylation machinery to an intermediate polyadenylation site, resulting in the elimination of the miR-145-5p binding site. Taken together, our data support the notion that the tumor suppressive activity of miR-145-5p on TWIST1 translation, consequently on EMT, self-renewal, and migration, depends on the CPEB1 expression status of the cancer cell. A preliminary prospective study using clinical samples suggests that reconsidering the relative status of miR-145-5p/TWIST1 and CPEB1 in the tumors of prostate cancer patients may bear prognostic value.

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