TFAP2A is a component of the ZEB1/2 network that regulates TGFB1-induced epithelial to mesenchymal transition

Abstract

BackgroundThe 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.MethodsFrom 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.ResultsWe 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.ConclusionsOur study reveals that TFAP2A is a conserved component of the core network that regulates EMT, acting as a repressor of many genes, including ZEB2.ReviewersThis article has been reviewed by Dr. Martijn Huynen and Dr. Nicola Aceto.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-017-0180-7) contains supplementary material, which is available to authorized users.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells

“…TFAP2A has been implicated in cancer proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) [ 33 , 34 ]. However, it remains unclear whether TFAP2A is involved in tumor-induced angiogenesis.…”

“…Previous studies reported that TFAP2A promotes EMT procession by regulating TGF-β signaling in cancer cells [ 33 ] and TFAP2A regulates tumor growth via hypoxia inducible factor-1a (HIF-1a) signaling in nasopharyngeal carcinoma and NSCLC [ 34 , 41 ], whereas the HIF-1a pathway has been confirmed to promote angiogenesis [ 42 ]. To validate the role of TFAP2A in anlotinib resistance, we performed TFAP2A knockdown in AR cells and found that tumor-induced angiogenesis was decreased in AR cells by TFAP2A knockdown.…”

Effect of Exposure to Seminal Plasma Through Natural Mating in Cattle on Conceptus Length and Gene Expression

“…The participation of TFGB3 in embryogenesis can be related to its role in the epithelial-mesenchymal transitions (EMT), which enables cell movement and morphogenesis (Zavadil and Böttinger, 2005). During gastrulation, EMT is observed in the generation of the primitive mesoderm, the cell migration into the primitive node and the establishment of the three embryonic layers (Blomberg et al, 2008;Dimitrova et al, 2017). CITED1 (or MSG1), which encodes for the transcriptional factor Cbp/p300-interacting transactivator 1, has been described to be involved during embryogenesis (Dunwoodie et al, 1998;Gerstner and Landry, 2007) and placentation (Rodriguez et al, 2004;Sparrow et al, 2009) in mice.…”

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

“…Although a vast majority of the studies conducted so far have portrayed AP-2α as a regulator of lineage specification during embryogenesis and cancer development and progression in adults (Eckert et al, 2005;Kolat et al, 2019), there is indication that AP-2α may play a key role in cellular fibrogenic response. AP-2α can promote epithelial-mesenchymal transition (EMT), a process critical to tissue fibrosis, by up-regulating TGF-β expression (Zhang et al, 2017) and by forming a complex with ZEB1/2, the E-box binding transcriptional regulators of EMT (Dimitrova et al, 2017). Ross et al (2019) have recently reported that deletion of TFAP2A (the gene encoding AP-2α) significantly attenuates the TGF-β induced maturation of myofibroblasts although the underlying mechanism is unclear.…”