required to repress the epithelial phenotype (reviewed in [39]). For
example, Snail repression of the CDH1 locus involves the DNA
methyltransferase (DNMT) G9a [40], the histone demethylase
LSD1 [41], or histone deacetylase 1 (HDAC1) and HDAC2 in
complex with either mSin3a [42] or polycomb repressor complex
2 components including enhancer of zeste homolog 2 (EZH2)
[43, 44]. Accordingly, ectopic expression of these TFs in epithelial
cells is often sufficient to suppress the epithelial program and invoke
mesenchymal features, thus leading to the designation
EMT-inducing TFs (EMT-TFs).
The action of EMT-TFs is not restricted to E-cadherin. ZEB1
binds to the promoters of, and represses, the Crumbs polarity
complex components Crumbs3 (Crb3) and Pals1-associated tight
junction protein (PATJ), and the Scribble complex components
human Lethal giant larvae homolog 2 (HUGL2) [45] and Lethal
giant larvae 2 (LGL2) [46], whereas ZEB2 represses CLDN4 and
ZO-3 [47]. Similarly, Snail represses expression of Crb3 [48],
epithelial cytoskeletal components KRT17, KRT18 and the epithelial apical recycling endosomal component Rab25 [49] and the
tight junction components occludin [50] and CLDN3, 4 and
7 [51], and Snail and Slug represses CLDN1 [52]. Therefore,
EMT-TFs can suppress multiple genes required for the epithelial
phenotype. Consequently, EMT-TFs induce the progressive loss of
epithelial junctional integrity leading to acquisition of a mesenchymal state.
Numerous signaling pathways converge on EMT-TFs to initiate EMT, including receptor tyrosine kinase (RTK)-mediated signaling (e.g., fibroblast growth factor (FGF)-FGF receptor (FGFR)
interactions), transforming growth factor beta (TGF-β) signaling,
Wnt/β-catenin signaling, and vascular endothelial growth factor
signaling; the precise signals are highly dependent on the cell-,
tissue-, and developmental-context in which EMT occurs (reviewed
in [53]).
CDH1 downregulation is not an absolute requirement for
EMT. During chick gastrulation, ingressing epiblast cells retain
E-cadherin despite increased migratory ability [8], and dissemination of mammary epithelial cells in 3D-culture driven by ectopic
Twist expression increases migration but without loss of E-cadherin
[54]. Numerous studies suggest that cells that maintain epithelial
features but exhibit intermediate expression of mesenchymal markers, termed partial-EMT, retain a plasticity that better allows
reversion to the epithelial state via MET compared to cells that
have undergone full EMT. Loss of polarity and acquisition of
mesenchymal features through EMT is a hallmark of many invasive
carcinomas, and metastasis is the primary cause of death in cancer
patients [55]. However, the degree to which EMT contributes to
invasiveness is hotly debated [56, 57], and it is proposed that
retention of epithelial features via partial-EMT and collective,
48
John-Poul Ng-Blichfeldt and Katja Ro ¨ per
example, Snail repression of the CDH1 locus involves the DNA
methyltransferase (DNMT) G9a [40], the histone demethylase
LSD1 [41], or histone deacetylase 1 (HDAC1) and HDAC2 in
complex with either mSin3a [42] or polycomb repressor complex
2 components including enhancer of zeste homolog 2 (EZH2)
[43, 44]. Accordingly, ectopic expression of these TFs in epithelial
cells is often sufficient to suppress the epithelial program and invoke
mesenchymal features, thus leading to the designation
EMT-inducing TFs (EMT-TFs).
The action of EMT-TFs is not restricted to E-cadherin. ZEB1
binds to the promoters of, and represses, the Crumbs polarity
complex components Crumbs3 (Crb3) and Pals1-associated tight
junction protein (PATJ), and the Scribble complex components
human Lethal giant larvae homolog 2 (HUGL2) [45] and Lethal
giant larvae 2 (LGL2) [46], whereas ZEB2 represses CLDN4 and
ZO-3 [47]. Similarly, Snail represses expression of Crb3 [48],
epithelial cytoskeletal components KRT17, KRT18 and the epithelial apical recycling endosomal component Rab25 [49] and the
tight junction components occludin [50] and CLDN3, 4 and
7 [51], and Snail and Slug represses CLDN1 [52]. Therefore,
EMT-TFs can suppress multiple genes required for the epithelial
phenotype. Consequently, EMT-TFs induce the progressive loss of
epithelial junctional integrity leading to acquisition of a mesenchymal state.
Numerous signaling pathways converge on EMT-TFs to initiate EMT, including receptor tyrosine kinase (RTK)-mediated signaling (e.g., fibroblast growth factor (FGF)-FGF receptor (FGFR)
interactions), transforming growth factor beta (TGF-β) signaling,
Wnt/β-catenin signaling, and vascular endothelial growth factor
signaling; the precise signals are highly dependent on the cell-,
tissue-, and developmental-context in which EMT occurs (reviewed
in [53]).
CDH1 downregulation is not an absolute requirement for
EMT. During chick gastrulation, ingressing epiblast cells retain
E-cadherin despite increased migratory ability [8], and dissemination of mammary epithelial cells in 3D-culture driven by ectopic
Twist expression increases migration but without loss of E-cadherin
[54]. Numerous studies suggest that cells that maintain epithelial
features but exhibit intermediate expression of mesenchymal markers, termed partial-EMT, retain a plasticity that better allows
reversion to the epithelial state via MET compared to cells that
have undergone full EMT. Loss of polarity and acquisition of
mesenchymal features through EMT is a hallmark of many invasive
carcinomas, and metastasis is the primary cause of death in cancer
patients [55]. However, the degree to which EMT contributes to
invasiveness is hotly debated [56, 57], and it is proposed that
retention of epithelial features via partial-EMT and collective,
48
John-Poul Ng-Blichfeldt and Katja Ro ¨ per