p38 MAPK Down-regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences

• Published in: The Journal of biological chemistry 2015-02, Vol.290 (7), p.4383-4397
• Main Authors: Arechederra, María, Priego, Neibla, Vázquez-Carballo, Ana, Sequera, Celia, Gutiérrez-Uzquiza, Álvaro, Cerezo-Guisado, María Isabel, Ortiz-Rivero, Sara, Roncero, Cesáreo, Cuenda, Ana, Guerrero, Carmen, Porras, Almudena
• Format: Article
• Language: English
• Subjects: cancer biology; cell signaling; fibulin 3; invasion; migration; p38 MAPK
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.582239

p38 MAPKs regulate migration and invasion. However, the mechanisms involved are only partially known. We had previously identified fibulin 3, which plays a role in migration, invasion, and tumorigenesis, as a gene regulated by p38α. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38α, p38γ, and p38δ down-regulate fibulin 3 expression. p38α has a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by the DNA methylase, DNMT3A, which is down-regulated in cells lacking p38α, but once re-introduced represses Fibulin 3 expression. p38α through HuR stabilizes dnmt3a mRNA leading to an increase in DNMT3A protein levels. Moreover, by knocking-down fibulin 3, we have found that Fibulin 3 inhibits migration and invasion in MEFs by mechanisms involving p38α/β inhibition. Hence, p38α pro-migratory/invasive effect might be, at least in part, mediated by fibulin 3 down-regulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38α and/or p38β activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38α, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38α limits fibulin 3 expression, which might represent a negative feed-back loop. Background: p38α MAPK regulates migration/invasion. Results: p38α induces hypermethylation of Fibulin 3 gene regulatory sequences leading to Fibulin 3 down-regulation. This contributes to regulate migration and invasion in MEFs and HCT116 cells. Conclusion: p38α down-regulates fibulin 3 expression through promoter methylation to control p38α-mediated migration and invasion. Significance: To understand the function of new p38α targets in migration/invasion and tumorigenesis.