Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth

// David Vindrieux 1,2,3,4 , Guillaume Devailly 1,2,3,4 , Arnaud Augert 1,2,3,4 , Benjamin Le Calve 1,2,3,4 , Mylene Ferrand 1,2,3,4 , Pascal Pigny 5,6 , Lea Payen 1,2,3,4 , Gerard Lambeau 7 , Michael Perrais 5 , Sebastien Aubert 5,8 , Helene Simonnet 1,2,3,4 , Robert Dante 1,2,3,4 and David Bernard 1,2,3,4 1 Inserm U1052, Centre de Recherche en Cancerologie de Lyon, Lyon, France; 2 CNRS UMR5286, Lyon France; 3 Centre Leon Berard, Lyon, France; 4 Universite de Lyon, Lyon, France; 5 INSERM U837, Jean-Pierre Aubert Research Center, Lille, France; 6 Institut de Biochimie et Biologie Moleculaire Centre de Biologie Pathologie CHRU Lille, Lille, France; 7 Institut de Pharmacologie Moleculaire et Cellulaire, UMR6097, CNRS and Universite de Nice-Sophia Antipolis, Valbonne, France; 8 Institut de Pathologie, CHRU, Faculte de Medecine, Universite de Lille, Lille, France. Correspondence: David Bernard, email: // Keywords : VHL; MYC; HIF; PLA2R1; tumor suppressor Received : December 11, 2013 Accepted : January 16, 2014 Published : January 16, 2014 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.