Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth
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David Vindrieux1,2,3,4, Guillaume Devailly1,2,3,4, Arnaud Augert1,2,3,4, Benjamin Le Calvé1,2,3,4, Mylène Ferrand1,2,3,4, Pascal Pigny5,6, Léa Payen1,2,3,4, Gérard Lambeau7, Michael Perrais5, Sébastien Aubert5,8, Hélène Simonnet1,2,3,4, Robert Dante1,2,3,4 and David Bernard1,2,3,4
1 Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France;
2 CNRS UMR5286, Lyon France;
3 Centre Léon Bérard, Lyon, France;
4 Université de Lyon, Lyon, France;
5 INSERM U837, Jean-Pierre Aubert Research Center, Lille, France;
6 Institut de Biochimie et Biologie Moléculaire Centre de Biologie Pathologie CHRU Lille, Lille, France;
7 Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, CNRS and Université de Nice-Sophia Antipolis, Valbonne, France;
8 Institut de Pathologie, CHRU, Faculté de Médecine, Université de Lille, Lille, France.
David Bernard, email:
Keywords: VHL; MYC; HIF; PLA2R1; tumor suppressor
Received: December 11, 2013 Accepted: January 16, 2014 Published: January 16, 2014
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.
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