Posttranscriptional regulation of per1 underlies the oncogenic function of IREα

Olivier Pluquet, Nicolas Dejeans, Marion Bouchecareilh, Stephanie Lhomond, Raphael Pineau, Arisa Higa, Maylis Delugin, Chantal Combe, Sandrine Loriot, Gaelle Cubel, Nathalie Dugot-Senant, Anne Vital, Hugues Loiseau, Sara J.C. Gosline, Said Taouji, Michael Hallett, Jann N. Sarkaria, Keith Anderson, Wenting Wu, Fausto J. RodriguezJean Rosenbaum, Frederic Saltel, Martin E. Fernandez-Zapico, Eric Chevet

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1a. Analysis of the mechanism shows that IRE1a endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1a signaling using either siRNA-mediated silencing or a dominantnegative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-a substrate, thereby pointing toward an increased IRE1a activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.

Original languageEnglish (US)
Pages (from-to)4732-4743
Number of pages12
JournalCancer research
Volume73
Issue number15
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pluquet, O., Dejeans, N., Bouchecareilh, M., Lhomond, S., Pineau, R., Higa, A., Delugin, M., Combe, C., Loriot, S., Cubel, G., Dugot-Senant, N., Vital, A., Loiseau, H., Gosline, S. J. C., Taouji, S., Hallett, M., Sarkaria, J. N., Anderson, K., Wu, W., ... Chevet, E. (2013). Posttranscriptional regulation of per1 underlies the oncogenic function of IREα. Cancer research, 73(15), 4732-4743. https://doi.org/10.1158/0008-5472.CAN-12-3989