1A) Interestingly, the core components of PRC2, including EZH2,

1A). Interestingly, the core components of PRC2, including EZH2, SUZ12, EED, and RBBP7, were simultaneously up-regulated in human HCCs (Fig. 1B; Supporting Fig. 1B). The primary function of PRC2 is to induce epigenetic transcriptional repression by way of H3K27me3.8 EZH2 is the H3K27 methyltransferase that functions as the catalytic subunit of PRC28 and the presence of other PRC2 protein

subunits is functionally essential for the enzymatic activity of EZH2.24 The expression of each individual PRC2 component was found to correlate positively with EZH2 (Supporting Fig. 1C), indicating that up-regulation of PRC2 may play a critical Decitabine purchase role in HCC development. Up-regulation of PRC2 in HCC prompted us to further investigate its implication in HCC development. Because EZH2 is the only histone methyltransferase of the complex, we reasoned that its contribution by way of its enzymatic activity should be more widespread than other PRC2 protein subunits. Thus, later parts of our study were concentrated on EZH2 to represent PRC2 dysregulation. Up-regulation of EZH2 in HCCs was confirmed by qRT-PCR in 59-paired primary HCCs and five normal human liver samples (Fig. 1C; Supporting Fig. 2A); and by immunohistochemistry in tissue microarrays consisted of 108-paired primary HCCs Selleckchem INK128 (Fig. 1D; Supporting

Fig. 2B). However, EZH1, a protein homolog of EZH2 that also promotes methylation of H3K27 in human embryonic stem (hES) cells,25 was not up-regulated in our HCC samples (Supporting Fig. 2C). This result further supports a specific function of EZH2 containing PRC2 in liver carcinogenesis. Hepatocarcinogenesis involves multiple stages where normal liver can develop background diseases such as chronic hepatitis and cirrhosis, then progresses to early HCC (pTNM stages I and II) and advanced HCC (pTNM stages III and IV). Interestingly,

EZH2 Teicoplanin expression increased gradually with disease progression from normal liver through chronic hepatitis and/or cirrhosis to early and then advanced HCC (Fig. 1E). Increased expression of EZH2 was also significantly associated with various metastatic features of HCC, including the presence of venous invasion (P = 0.043), direct liver invasion (P = 0.014), and the absence of tumor encapsulation (P = 0.043) (Fig. 1F; Supporting Table 5). These findings highlight the pathological significance of EZH2 up-regulation during liver cancer development. After revealing the positive correlation between EZH2 expression and HCC aggressiveness, we decided to investigate the cellular and molecular effects of EZH2 up-regulation in HCC cells. Differential EZH2 expression was detected across a panel of HCC cell lines (Supporting Fig. 2D). Ectopic overexpression of EZH2 increased the levels of H3K27me3 in PLC/PRF/5 cells, which had low endogenous EZH2 levels (Supporting Fig. 3A).

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