Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT
Antonio Díaz-López
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
*A.D.L. and J.D.M. contributed equally to this work.
Search for more papers by this authorJuan Díaz-Martín
Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
*A.D.L. and J.D.M. contributed equally to this work.
Search for more papers by this authorGema Moreno-Bueno
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Fundación MD Anderson Internacional Madrid, Translational Research Laboratory, Madrid, Spain
Search for more papers by this authorEva P. Cuevas
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Instituto de Investigación Sanitaria La Paz, Cancer and Human Molecular Genetics Program, IdiPAZ, Spain
Search for more papers by this authorVanesa Santos
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Instituto de Investigación Sanitaria La Paz, Cancer and Human Molecular Genetics Program, IdiPAZ, Spain
Search for more papers by this authorDavid Olmeda
Centro Nacional de Investigaciones Oncológicas, Molecular Oncology Program, ISCIII, Madrid, Spain
Search for more papers by this authorFrancisco Portillo
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Search for more papers by this authorCorresponding Author
José Palacios
Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
Department of Pathology, Hospital Universitario Ramón y Cajal, IRyCIS, RETICC, Madrid, Spain
Correspondence to: Amparo Cano, Departamento de Bioquímica, UAM. c/ Arzobispo Morcillo, 2, 28029 Madrid, Spain, E-mail: [email protected] or José Palacios, Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Amparo Cano
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Correspondence to: Amparo Cano, Departamento de Bioquímica, UAM. c/ Arzobispo Morcillo, 2, 28029 Madrid, Spain, E-mail: [email protected] or José Palacios, Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. E-mail: [email protected]Search for more papers by this authorAntonio Díaz-López
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
*A.D.L. and J.D.M. contributed equally to this work.
Search for more papers by this authorJuan Díaz-Martín
Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
*A.D.L. and J.D.M. contributed equally to this work.
Search for more papers by this authorGema Moreno-Bueno
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Fundación MD Anderson Internacional Madrid, Translational Research Laboratory, Madrid, Spain
Search for more papers by this authorEva P. Cuevas
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Instituto de Investigación Sanitaria La Paz, Cancer and Human Molecular Genetics Program, IdiPAZ, Spain
Search for more papers by this authorVanesa Santos
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Instituto de Investigación Sanitaria La Paz, Cancer and Human Molecular Genetics Program, IdiPAZ, Spain
Search for more papers by this authorDavid Olmeda
Centro Nacional de Investigaciones Oncológicas, Molecular Oncology Program, ISCIII, Madrid, Spain
Search for more papers by this authorFrancisco Portillo
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Search for more papers by this authorCorresponding Author
José Palacios
Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
Department of Pathology, Hospital Universitario Ramón y Cajal, IRyCIS, RETICC, Madrid, Spain
Correspondence to: Amparo Cano, Departamento de Bioquímica, UAM. c/ Arzobispo Morcillo, 2, 28029 Madrid, Spain, E-mail: [email protected] or José Palacios, Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. E-mail: [email protected]Search for more papers by this authorCorresponding Author
Amparo Cano
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, RETICC, Madrid, Spain
Correspondence to: Amparo Cano, Departamento de Bioquímica, UAM. c/ Arzobispo Morcillo, 2, 28029 Madrid, Spain, E-mail: [email protected] or José Palacios, Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. E-mail: [email protected]Search for more papers by this authorAbstract
Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR-200 family regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo.
Abstract
What's new?
Epithelial-mesenchymal transition (EMT) is involved in the initiation of metastasis and is regulated by transcription factors (EMT-TFs) that are themselves regulated by miRNAs. The roles of the different EMT-TFs and their functional relationships, however, are poorly understood. Here, the EMT-TFs Snail1 and Zeb1 were found to play an essential role in EMT induction, while mesenchymal phenotype was maintained by continuous Snail1 and Snail2 expression. Snail1 controlled and maintained the mesenchymal phenotype through CpG DNA hypermethylation of miR-200 loci. Hypermethylated miR-200 family members may serve as surrogate markers in the treatment or prognosis of carcinosarcomas.
Supporting Information
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