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2017 ; 12
(1
): 8
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TFAP2A is a component of the ZEB1/2 network that regulates TGFB1-induced
epithelial to mesenchymal transition
#MMPMID28412966
Dimitrova Y
; Gruber AJ
; Mittal N
; Ghosh S
; Dimitriades B
; Mathow D
; Grandy WA
; Christofori G
; Zavolan M
Biol Direct
2017[Apr]; 12
(1
): 8
PMID28412966
show ga
BACKGROUND: The transition between epithelial and mesenchymal phenotypes (EMT)
occurs in a variety of contexts. It is critical for mammalian development and it
is also involved in tumor initiation and progression. Master transcription factor
(TF) regulators of this process are conserved between mouse and human. METHODS:
From a computational analysis of a variety of high-throughput sequencing data
sets we initially inferred that TFAP2A is connected to the core EMT network in
both species. We then analysed publicly available human breast cancer data for
TFAP2A expression and also studied the expression (by mRNA sequencing), activity
(by monitoring the expression of its predicted targets), and binding (by
electrophoretic mobility shift assay and chromatin immunoprecipitation) of this
factor in a mouse mammary gland EMT model system (NMuMG) cell line. RESULTS: We
found that upon induction of EMT, the activity of TFAP2A, reflected in the
expression level of its predicted targets, is up-regulated in a variety of
systems, both murine and human, while TFAP2A's expression is increased in more
"stem-like" cancers. We provide strong evidence for the direct interaction
between the TFAP2A TF and the ZEB2 promoter and we demonstrate that this
interaction affects ZEB2 expression. Overexpression of TFAP2A from an exogenous
construct perturbs EMT, however, in a manner similar to the downregulation of
endogenous TFAP2A that takes place during EMT. CONCLUSIONS: Our study reveals
that TFAP2A is a conserved component of the core network that regulates EMT,
acting as a repressor of many genes, including ZEB2. REVIEWERS: This article has
been reviewed by Dr. Martijn Huynen and Dr. Nicola Aceto.