rather than individual, delamination from primary tumors renders
cancer cells more prone to distant metastatic colonization, consistent with the identification of partial-EMT states of circulating
tumor cells and the polyclonal nature of metastatic tumors
observed in patients [58, 59]. Understanding how EMT and
MET programs are dysregulated during carcinoma progression is
thus likely to be critical to developing better therapeutic approaches
for cancer.
The identification of EMT-TFs supports the hypothesis that
the evolutionary emergence of the mesenchymal phenotype was
driven by the innovation of direct transcriptional repression of the
epithelial program [15]; such EMT-TFs are able to overcome the
activity of ubiquitous TFs that drive expression of epithelial-specific
genes such as CDH1. Accordingly, EMT-TFs are expressed in a
spatial-temporal pattern during vertebrate embryogenesis consistent with the appearance of migratory cells.
5 Cellular Strategies to Restrict EMT
Of critical importance to developmental EMT events is their shortlived nature, permitting re-establishment of epithelial tissues at the
correct time and place for normal tissue patterning. It is therefore
surprising that relatively little attention has been given to mechanisms of MET compared to EMT. Cells employ several mechanisms
to inhibit the activity of EMT-TFs, providing temporally controlled
de-repression of epithelial genes and reversion to an epithelial state.
These include specific TFs that directly repress EMT-TFs to induce
MET (which we designate MET-TFs, summarized in Table 1),
micro-RNAs, and post-translational modifications of EMT-TFs,
regulated in a tissue-specific manner to enable precise spatiotemporal control over EMT-MET events during development and
in adult tissue maintenance.
5.1 Grainy-Head
Family
TFs of the Grainy-head family, including Grainyhead (grh) in Drosophila and Grainy-head like (GRHL1, 2, and 3) in humans and
mice, have emerged as TFs with potentially broad roles in establishing and maintaining the epithelial phenotype in developing and
adult epithelial tissues. GRLH2 null mice show defects in neural
tube closure, which requires establishment of epithelial cell-cell
adhesion, due to disrupted expression of adhesion molecules
including E-cadherin and CLDN4, 6, and 7 [60]. During kidney
development, GRHL2 co-expresses with E-cadherin in the distal
nephron, collecting duct, and ureteric bud epithelium
[61, 62]. Notably, GRHL2 binds to enhancer elements in intron
2 of the CDH1 gene to activate promoter activity through chromatin looping [61], suggesting that tissue-specific GRHL2 expression may contribute to epithelial-specific CDH1 activation during
Mechanisms of MET in Development and Cancer
49
cancer cells more prone to distant metastatic colonization, consistent with the identification of partial-EMT states of circulating
tumor cells and the polyclonal nature of metastatic tumors
observed in patients [58, 59]. Understanding how EMT and
MET programs are dysregulated during carcinoma progression is
thus likely to be critical to developing better therapeutic approaches
for cancer.
The identification of EMT-TFs supports the hypothesis that
the evolutionary emergence of the mesenchymal phenotype was
driven by the innovation of direct transcriptional repression of the
epithelial program [15]; such EMT-TFs are able to overcome the
activity of ubiquitous TFs that drive expression of epithelial-specific
genes such as CDH1. Accordingly, EMT-TFs are expressed in a
spatial-temporal pattern during vertebrate embryogenesis consistent with the appearance of migratory cells.
5 Cellular Strategies to Restrict EMT
Of critical importance to developmental EMT events is their shortlived nature, permitting re-establishment of epithelial tissues at the
correct time and place for normal tissue patterning. It is therefore
surprising that relatively little attention has been given to mechanisms of MET compared to EMT. Cells employ several mechanisms
to inhibit the activity of EMT-TFs, providing temporally controlled
de-repression of epithelial genes and reversion to an epithelial state.
These include specific TFs that directly repress EMT-TFs to induce
MET (which we designate MET-TFs, summarized in Table 1),
micro-RNAs, and post-translational modifications of EMT-TFs,
regulated in a tissue-specific manner to enable precise spatiotemporal control over EMT-MET events during development and
in adult tissue maintenance.
5.1 Grainy-Head
Family
TFs of the Grainy-head family, including Grainyhead (grh) in Drosophila and Grainy-head like (GRHL1, 2, and 3) in humans and
mice, have emerged as TFs with potentially broad roles in establishing and maintaining the epithelial phenotype in developing and
adult epithelial tissues. GRLH2 null mice show defects in neural
tube closure, which requires establishment of epithelial cell-cell
adhesion, due to disrupted expression of adhesion molecules
including E-cadherin and CLDN4, 6, and 7 [60]. During kidney
development, GRHL2 co-expresses with E-cadherin in the distal
nephron, collecting duct, and ureteric bud epithelium
[61, 62]. Notably, GRHL2 binds to enhancer elements in intron
2 of the CDH1 gene to activate promoter activity through chromatin looping [61], suggesting that tissue-specific GRHL2 expression may contribute to epithelial-specific CDH1 activation during
Mechanisms of MET in Development and Cancer
49