Figure 2.
The biology of EZH2 in breast cancer. EZH2 gene expression is regulated by the HIF, E2F, and RAF/ERK/Elk pathways. Increased levels of EZH2 have been linked to H3K27 trimethylation (H3K27me3) on promoter regions of several genes (RAD51, RUNX3, CDKN1C (p57 KIP2), FOXC1, and CDH1 (E-cadherin)) whose expression is decreased. Reduced levels of RAD51 lead to the activation of Raf1/ERK and β-catenin signaling. Transcription of the CDKN1A gene is under RUNX3 control and lower concentrations of RUNX3 result in lower p21WAF/Cip1 levels, which fail to fully block the cell cycle. The CDKN1C gene encodes the cyclin-dependent kinase inhibitor p57KIP2, a strong inhibitor of cyclinE1 and CDK2 complexes. Expression of the CDKN1C gene is regulated through H3K27me3 of its promoter. Reduction of p57KIP2 leads to accelerated G1-S transition, which has been suggested to support breast cancer progression. Accumulation of H3K27me3 in the promoters of the FOXC1 gene, a fork head family transcription factor used in developmental programs, and the CDH1 gene, that encodes E-cadherin, has been observed in breast cancer cell lines. A decrease of FOXC1 and E-cadherin would be in agreement with enhanced cell invasion and metastasis.