mesendoderm [86]. Sox3-Slug antagonism thus controls cell adhesion and behavior to define cell territories rather than directly
inducing cell fate. This is consistent with the role of Snail in
controlling cell migration during gastrulation rather than being a
specific mesoderm inducer [87]. Moreover, Sox3 loss in mouse ES
cells leads to de-repression of Snail and downregulation of
E-cadherin, and Sox3 overexpression in human breast cancer cell
lines decreases Snail and induces CDH1 [86], supporting a role for
Sox3 as a MET-TF.
Together, these studies indicate the existence of TFs that are
able to restrict EMT both during developmental processes and in
adult epithelial homeostasis. Of note, the evolutionary origins of
the Grh family appear to pre-date the emergence of the Snail family
[88, 89]. Thus, the pre-existence of mechanisms to maintain epithelial features could have provided a permissive background to
allow EMT-TFs to emerge, ensuring induction of EMT is temporally controlled to allow proper patterning during development.
Signaling mechanisms upstream of MET-TFs are still poorly
characterized. Intriguingly, cyclic AMP (cAMP)-mediated signaling has long been recognized to promote epithelial characteristics
in cultured epithelial cells. A recent study identified a cAMPprotein kinase A (PKA)-mediated pathway as able to restore epithelial characteristics in mesenchymal breast cancer cells via direct
recruitment of the H3K9 demethylase PHF2, which binds to and
de-represses a range of epithelial genes including CDH1, CDH3,
and CLDN4 [90]. An interesting possibility is that global target
gene specificity of PHF2 is mediated by MET-TFs such as those
described above; however, this is yet to be formally investigated.
5.6 Micro-RNA
Control of EMT-TFs
Inhibition of EMT-TFs by micro-RNAs has emerged as an additional means by which cells exert control over EMT. In early
studies, the miR-200 family, consisting of two closely related
sub-families (comprising miR-200a and miR-141, and miR-200b,
miR-200c and miR-429), was shown to directly inhibit ZEB1/2 to
maintain E-cadherin expression in epithelial human cancer cell lines
[91]. Ectopic expression of miR-200a and miR-200c induces MET
in mesenchymal cancer cells [91] and prevents TGF-β-induced
EMT in epithelial cells [92]. In turn, ZEB1/2 represses miR-200
family members, indicating a negative feedback loop [93, 94],
allowing tight temporal control over EMT. A multitude of other
miRNAs has since been demonstrated to control expression of both
ZEB1/ZEB2 and other EMT-TFs, providing an additional layer of
complexity to control of EMT (reviewed in [95]).
Mechanisms of MET in Development and Cancer
53
inducing cell fate. This is consistent with the role of Snail in
controlling cell migration during gastrulation rather than being a
specific mesoderm inducer [87]. Moreover, Sox3 loss in mouse ES
cells leads to de-repression of Snail and downregulation of
E-cadherin, and Sox3 overexpression in human breast cancer cell
lines decreases Snail and induces CDH1 [86], supporting a role for
Sox3 as a MET-TF.
Together, these studies indicate the existence of TFs that are
able to restrict EMT both during developmental processes and in
adult epithelial homeostasis. Of note, the evolutionary origins of
the Grh family appear to pre-date the emergence of the Snail family
[88, 89]. Thus, the pre-existence of mechanisms to maintain epithelial features could have provided a permissive background to
allow EMT-TFs to emerge, ensuring induction of EMT is temporally controlled to allow proper patterning during development.
Signaling mechanisms upstream of MET-TFs are still poorly
characterized. Intriguingly, cyclic AMP (cAMP)-mediated signaling has long been recognized to promote epithelial characteristics
in cultured epithelial cells. A recent study identified a cAMPprotein kinase A (PKA)-mediated pathway as able to restore epithelial characteristics in mesenchymal breast cancer cells via direct
recruitment of the H3K9 demethylase PHF2, which binds to and
de-represses a range of epithelial genes including CDH1, CDH3,
and CLDN4 [90]. An interesting possibility is that global target
gene specificity of PHF2 is mediated by MET-TFs such as those
described above; however, this is yet to be formally investigated.
5.6 Micro-RNA
Control of EMT-TFs
Inhibition of EMT-TFs by micro-RNAs has emerged as an additional means by which cells exert control over EMT. In early
studies, the miR-200 family, consisting of two closely related
sub-families (comprising miR-200a and miR-141, and miR-200b,
miR-200c and miR-429), was shown to directly inhibit ZEB1/2 to
maintain E-cadherin expression in epithelial human cancer cell lines
[91]. Ectopic expression of miR-200a and miR-200c induces MET
in mesenchymal cancer cells [91] and prevents TGF-β-induced
EMT in epithelial cells [92]. In turn, ZEB1/2 represses miR-200
family members, indicating a negative feedback loop [93, 94],
allowing tight temporal control over EMT. A multitude of other
miRNAs has since been demonstrated to control expression of both
ZEB1/ZEB2 and other EMT-TFs, providing an additional layer of
complexity to control of EMT (reviewed in [95]).
Mechanisms of MET in Development and Cancer
53