**7.2 EZH2**

Polycomb repressive complex 2 (PRC2) is another modifier of the chromatin structure, which determines the activity of gene expression. PRC2 primarily regulates gene expression by inducing the methylation on lysine 9 and lysine 27 of histone 3, and plays important roles during development and tumorigenesis. In this complex, EZH2 is the catalytic subunit directly involves in transferring methyl-group to the histone tails (Kirmizis et al., 2004). The level of EZH2 is important in determining the PRC2 activity in cells. EZH2 regulates cell proliferation, and its expression is often augmented during tumorigenesis. EZH2 overexpression can be observed in many cancers, including prostate, breast and pancreas cancer, and most often high level of EZH2 is correlated to aggressiveness of the malignancies (Tsang et al., 2011). EZH2 is rarely detected in normal hepatocytes, but is frequently detected in HCC cell lines and HCC tissues (Chen et al., 2007).

EZH2 is involved in numerous cellular processes and signaling pathways and evidences suggested that EZH2 promotes cancer development by repressing diverse tumorsuppressors. Recently, EZH2 reportedly activated Wnt signaling in HCC. Concurrent overexpression of EZH2 and β-catenin was observed in more than 30% of human HCC, which is associated with tumor progression (Cheng et al., 2011). In HCC cells, EZH2 is found to frequently occupy the promoter of numerous Wnt pathway antagonists. As such, these antagonists are silenced, relieving the inhibitory effect on Wnt/β-catenin signaling. In immortalized hepatocytes, ectopic expression of EZH2 activated Wnt/β-catenin signaling and triggered cell proliferation (Cheng et al., 2011). Conversely, downregulation of EZH2 inhibited β-catenin signaling, resulting in the retardation of HCC cell growth. Study showed that knockdown of EZH2 by lentivirus-based shRNA inhibited tumor growth in vivo (Chen et al., 2007), demonstrating a potent effect against HCC by targeting EZH2. The significance of EZH2 role in HCC suggested that strategies built around EZH2 is definitely advantageous.

EZH2 is theoretically suitable for pharmalogical targeting as it contains a SET domain responsible for the histone methyltransferase activity. Targeting of the enzymatic domain is proved to reduce histone methylation and de-repress expression of tumor suppressor genes. In addition to the catalytic domain, there are two N-terminal domains mediating proteinprotein interactions and promoting nuclear localization within EZH protein, which are druggable targets in ablating EZH2 activity. Disruption of the PRC2 is also effective to attenuate the tumorigenic effect of EZH2. The formation of functional PRC2 requires other protein subunits such as EED and SUZ12. Report revealed that the use of agent disrupting PRC2 subunits is a relevant way to affect PRC2 function (Tan et al., 2007). Although currently there is no EZH2 specific inhibitor, but agent such as DZnep is also able to deplete the cellular EZH2, inhibit EZH2 functions and lower the H3K27 trimethylation level (Chiba et al., 2011). This fundamental knowledge surely enables researchers to design potent agents to target EZH2 in HCC.
