The silencing of E-cadherin expression by hypermethylation is a common event in cancer.
DNMTs target cytosine residues in CpG dinucleotides for methylation and have been identified in the repression of E-cadherin in normal and pathological contexts
such as colorectal cancer, gastric cancer and hepatocellular carcinomas.
Multiple signaling pathways involved in EMT and tumorigenesis activate DNMTs, e.g., ras43 and TGF-b.
DNMTs bind several histone remodeling enzymes, such as Sirtuin and G9a.
However, SNAI1 has been shown to be linked to DNMT1, notably in association with G9a and Suv39H1.
Cooperation between Polycomb proteins and EMT-inducing transcription factors.
The polycomb proteins are part of repressor complexes that inhibit gene expression through chromatin remodeling.
The polycomb repressive complex 2 (PRC2) recruits PRC1 after chromatin methylation at H3K27 through enhancer of EZH2, a histone H3 lysine-27-specific methyltransferase.
Both, PRC1 and PRC2 have been shown to interact with SNAI1 and TWIST1 to promote EMT.
SNAI1 is stabilized through its interaction with the PRC1 component BMI1 and interacts with EZH2 and Suz12 to repress CDH1 expression.
Interestingly, EZH2 also participates in TGFb1 signaling, a potent inducer of EMT.
BMI-1 can also interact with TWIST to induce EMT.
Repression of E-cadherin by SNAI1/TWIST1 involves the recruitment of histone remodeling proteins to the promoter, where SNAI1 interacts with histone deacetylase HDAC1 and HDAC2.
The intricate interactions of EMT-inducing transcription factors and chromatin remodeling complexes PRC1 and PRC2 may offer novel approaches to control EMT and thus cell adhesion in cancer cells via a plethora of new drug, such as HDACs and DNMT inhibitors.
e_re1383( EMT ):
EZH1 and EZH2 are targets of HEYs-mediated transcriptional repression.
This finding suggests that TGFB-activated EMT could be controlled through structural histone modification.
c_re946:( Cell cycle ) PMID:14532106
In compartment: Gene compartment
In compartment: Nucleus
Participates in complexes:
Participates in reactions:
As Reactant or Product:
- E2F2_alone@Cytoplasm → gEZH2@Gene compartment
- E2F3_alone@Cytoplasm → gEZH2@Gene compartment
- E2F4@Nucleus → gEZH2@Gene compartment
- E2F1_alone@Cytoplasm → gEZH2@Gene compartment
- gEZH2@Nucleus → rEZH2@Nucleus