The class I bHLH factors E2-2A and E2-2B regulate EMT.
Functional loss of the cell-cell adhesion molecule E-cadherin is an essential event for epithelial-mesenchymal transition (EMT), a process that allows cell migration during embryonic development and tumour invasion. In most carcinomas, transcriptional repression has emerged as the main mechanism responsible for E-cadherin downregulation. Here, we report the identification of class I bHLH factor E2-2 (TCF4/ITF2) as a new EMT regulator. Both isoforms of E2-2 (E2-2A and E2-2B) induce a full EMT when overexpressed in MDCK cells but without affecting the tumorigenic properties of parental cells, in contrast to other EMT inducers, such as Snail1 or class I bHLH E47. E-cadherin repression mediated by E2-2 is indirect and independent of proximal E-boxes of the promoter. Knockdown studies indicate that E2-2 expression is dispensable for maintenance of the EMT driven by Snail1 and E47. Comparative gene-profiling analysis reveals that E2-2 factors induce similar, yet distinct, genetic programs to that induced by E47 in MDCK cells. These results, together with the embryonic expression pattern of Tcf4 and E2A (which encodes E12/E47), support a distinct role for E2-2 and suggest an interesting interplay between E-cadherin repressors in the regulation of physiological and pathological EMT processes.
Sobrado
Verónica R
VR
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain.
Moreno-Bueno
Gema
G
Cubillo
Eva
E
Holt
Liam J
LJ
Nieto
M Angela
MA
Portillo
Francisco
F
Cano
Amparo
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004285:Dogs; D004622:Embryo, Mammalian / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C544912:TCF7L1 protein, human; C544894:TCF7L2 protein, human; C544913:Tcf7l1 protein, mouse; C544895:Tcf7l2 protein, mouse