ABSTRACT
The Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of the Polycomb-Repressive Complex 2 (PRC2) that is centrally involved in epigenetically regulating the gene transcription programs during development and cellular differentiation. EZH2 is abnormally expressed in a wide range of cancers with levels of expression that are correlated with the severity and aggressiveness of the tumor. The importance of EZH2 in controlling the balance between proliferation and differentiation is therefore of paramount importance. EZH2 acts mainly through trimethylation of histone H3 lysine27 (H3K27me3), which is associated with transcriptional repression. This modification also facilitates the recruitment of other key epigenetic players such as the Polycomb Repressor Complex 1 (PRC1), DNA methyltransferases, and histone deacetylases that together produce chromatin compaction and enhanced transcriptional repression. Similarly important is the role of EZH2 in controlling the expansion and differentiation of tumor-initiating Cancer Stem Cells (CSCs). Through these mechanisms, EZH2 controls diverse phenotypic features of cancer, including proliferation, invasiveness, metastasis, and resistance to cell death. In the many tumor types reviewed in this chapter, the pharmacological inhibition of EZH2 by 3-deazaneplanocin A (DZNep) singly or in combination with other epigenetic drugs successfully leads to the reversal of the malignant phenotype.
