A non-coding function of TYRP1 mRNA promotes melanoma growth

David Gilot (1) , Mélodie Migault (1) , Laura Bachelot (1) , Fabrice Journé (2) , Aljosja Rogiers (3) , Emmanuelle Donnou-Fournet (1) , Ariane Mogha (1) , Nicolas Mouchet (1) , Marie-Laure Pinel-Marie (4) , Bernard Mari (5, 6) , Tristan Montier (7, 8) , Sébastien Corre (1) , Arthur Gautron (1) , Florian Rambow (3) , Petra El Hajj (9) , Rania Ben Jouira (10) , Sophie Tartare-Deckert (10) , Jean-Christophe Marine (11, 9) , Brice Felden (4) , Ghanem Ghanem , Marie-Dominique Galibert (1, 12)

1 IGDR - Institut de Génétique et Développement de Rennes
2 Institut Jules Bordet [Bruxelles]
3 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
4 BRM - ARN régulateurs bactériens et médecine
5 IPMC - Institut de pharmacologie moléculaire et cellulaire
6 UNS - Université Nice Sophia Antipolis (1965 - 2019)
7 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
8 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
9 ULB - Université libre de Bruxelles
10 C3M - Centre méditerranéen de médecine moléculaire
11 Centre de Génétique Humaine
12 CHU Pontchaillou [Rennes]

Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma.

Keywords: MicroRNAs; Oxidoreductases; RNA; Messenger; Animals; Mice; Membrane Glycoproteins; Melanoma; Humans; Female; Cell Proliferation; Tumor; Binding Sites; Cell Line

Domains: Life Sciences [q-bio]; Genetics

David Gilot, Mélodie Migault, Laura Bachelot, Fabrice Journé, Aljosja Rogiers, et al.. A non-coding function of TYRP1 mRNA promotes melanoma growth. Nature Cell Biology, 2017, 19 (11), pp.1348-1357. ⟨10.1038/ncb3623⟩. ⟨hal-01647130⟩