title: p38 MAPK down-regulates fibulin 3 expression through methylation of gene regulatory sequences: role in migration and invasion.
abstract: 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.
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Arechederra
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: Neibla
authors.initials: N
authors.lastname: Priego
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vázquez-Carballo
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Sequera
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Gutiérrez-Uzquiza
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología-CSIC, Campus de Canto Blanco, 28049 Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Cerezo-Guisado
authors.affiliation: Centro de Investigación del Cáncer, IBMCC, Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortiz-Rivero
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.
authors.forename: Cesáreo
authors.initials: C
authors.lastname: Roncero
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología-CSIC, Campus de Canto Blanco, 28049 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cuenda
authors.affiliation: Centro de Investigación del Cáncer, IBMCC, Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain cguerrero@usal.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerrero
authors.affiliation: From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain, maporras@ucm.es.
authors.forename: Almudena
authors.initials: A
authors.lastname: Porras
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: C492278:Efemp1 protein, mouse; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D048308:Mitogen-Activated Protein Kinase 14
keywords: cancer biology; cell signaling; fibulin 3; invasion; migration; p38 MAPK