title: Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα.
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 IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative 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-α substrate, thereby pointing toward an increased IRE1α 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.
authors.affiliation: Inserm U1053, University of Bordeaux, 146 rue Leo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pluquet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lhomond
authors.forename: Raphael
authors.initials: R
authors.lastname: Pineau
authors.forename: Arisa
authors.initials: A
authors.lastname: Higa
authors.forename: Maylis
authors.initials: M
authors.lastname: Delugin
authors.forename: Chantal
authors.initials: C
authors.lastname: Combe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Loriot
authors.forename: Gaelle
authors.initials: G
authors.lastname: Cubel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dugot-Senant
authors.forename: Anne
authors.initials: A
authors.lastname: Vital
authors.forename: Hugues
authors.initials: H
authors.lastname: Loiseau
authors.forename: Sara J C
authors.initials: SJ
authors.lastname: Gosline
authors.forename: Said
authors.initials: S
authors.lastname: Taouji
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Keith
authors.initials: K
authors.lastname: Anderson
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saltel
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
mesh_terms: D000818:Animals; D001483:Base Sequence; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D056811:Unfolded Protein Response / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C539022:PER1 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases