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: David Vindrieux, Guillaume Devailly, Arnaud Augert, Benjamin Le Calvé, Mylène Ferrand, Pascal Pigny, Léa Payen, Gérard Lambeau, Michael Perrais, Sébastien Aubert, Hélène Simonnet, Robert Dante, David Bernard
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 4 Pg. 1004-13 (Feb 28 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24657971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• MYC protein, human
• PLA2R1 protein, human
• Proto-Oncogene Proteins c-myc
• Receptors, Phospholipase A2
• endothelial PAS domain-containing protein 1

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Female
• Heterografts
• Humans
• Kidney Neoplasms (genetics, metabolism, pathology)
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Receptors, Phospholipase A2 (genetics, metabolism)
• Signal Transduction
• Transfection