title: Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth.
abstract: Loss of secreted phospholipase A2 receptor (PLA2R1) has recently been found to render human primary cells more resistant to senescence whereas increased PLA2R1 expression is able to induce cell cycle arrest, cancer cell death or blockage of cancer cell transformation in vitro, suggesting that PLA2R1 displays tumor suppressive activities. Here we report that PLA2R1 expression strongly decreases in samples of human renal cell carcinoma (RCC). Knockdown of PLA2R1 increases renal cancer cell tumorigenicity supporting a role of PLA2R1 loss to promote in vivo RCC growth. Most RCC result from Von Hippel-Lindau (VHL) tumor suppressor loss-of-function and subsequent gain-of-function of the oncogenic HIF-2alpha/c-MYC pathway. Here, by genetically manipulating VHL, HIF-2alpha and c-MYC, we demonstrate that loss of VHL, stabilization of HIF-2alpha and subsequent increased c-MYC activity, binding and transcriptional repression, through induction of PLA2R1 DNA methylation closed to PLA2R1 transcriptional start site, results in decreased PLA2R1 transcription. Our results describe for the first time an oncogenic pathway leading to PLA2R1 transcriptional repression and the importance of this repression for tumor growth.
authors.affiliation: Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.forename: Guillaume
authors.initials: G
authors.lastname: Devailly
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.forename: Mylène
authors.initials: M
authors.lastname: Ferrand
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigny
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: Michael
authors.initials: M
authors.lastname: Perrais
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.forename: Hélène
authors.initials: H
authors.lastname: Simonnet
authors.forename: Robert
authors.initials: R
authors.lastname: Dante
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D054507:Receptors, Phospholipase A2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016271:Proto-Oncogene Proteins c-myc; D054507:Receptors, Phospholipase A2; D000099162:Endothelial PAS Domain-Containing Protein 1; C489427:MYC protein, human; C516360:PLA2R1 protein, human