Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

A'dem Bokhari; Vincent Jonchere; Anaïs Lagrange; Romane Bertrand; Magali Svrcek; Laetitia Marisa; Olivier Buhard; Malorie Greene; Anastasia Demidova; Jieshuang Jia; Eric Adriaenssens; Thierry Chassat; Denis S Biard; Jean-François Flejou; Fabrice Lejeune; Alex Duval; Ada Collura

doi:10.1038/s41389-018-0079-x

Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

Oncogenesis. 2018 Sep 19;7(9):70. doi: 10.1038/s41389-018-0079-x.

Authors

A'dem Bokhari¹, Vincent Jonchere¹, Anaïs Lagrange¹, Romane Bertrand¹, Magali Svrcek^{1

2}, Laetitia Marisa^{1

3}, Olivier Buhard¹, Malorie Greene¹, Anastasia Demidova¹, Jieshuang Jia⁴, Eric Adriaenssens⁵, Thierry Chassat⁶, Denis S Biard⁷, Jean-François Flejou^{1

2}, Fabrice Lejeune⁴, Alex Duval¹, Ada Collura⁸

Affiliations

¹ Sorbonne Université, UPMC Univ Paris 06, INSERM, UMRS 938, SIRIC CURAMUS, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche Saint Antoine, Paris, F-75012, France.
² AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France.
³ Programme "Cartes d'Identité des Tumeurs", Ligue Nationale Contre le Cancer, Paris, France.
⁴ Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Target Therapies, F-59000, Lille, France.
⁵ INSERM U908, Cell Plasticity and Cancer, University of Lille, 59655, Villeneuve d'Ascq, France.
⁶ Pasteur de Lille-PLEHTA (Plateforme d'expérimentation et de Haute Technologie Animale), 59019, Lille, France.
⁷ Centre d'Etude Atomique, Direction des Sciences du Vivant, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etude des Prions et des Infections Atypiques, Fontenay-aux-Roses, France.
⁸ Sorbonne Université, UPMC Univ Paris 06, INSERM, UMRS 938, SIRIC CURAMUS, Equipe Instabilité des Microsatellites et Cancer, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche Saint Antoine, Paris, F-75012, France. ada.collura@inserm.fr.

Abstract

Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC.