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  • Enhancer of Zeste Homolog EZH is a core


    Enhancer of Zeste Homolog 2 (EZH2) is a core component of the Polycomb Repressive Complex2 (PRC2) which also includes SUZ12 and EED. PRC2 represses gene transcription through trimethylation of Lys27 of histone H3 (H3K27), and contribute to the maintenance of cell identity, SB408124 regulation and oncogenesis [6,7]. Recently, increasing evidence reveals that EZH2 overexpression occurs in a variety of human malignancies including non small cell lung cancer [8], colorectal cancer [9], hepatocellular [10] and breast cancers [11]. More importantly, abnormalities of EZH2 expression were observed to correlate closely with tumor aggressiveness or poor patient prognosis. For example, EZH2-mediated inactivation of KLF2 blocks the tumor-suppressor features of the KLF2 and its growth-inhibitory features in both cellular and animal models [12]. Moreover, EZH2 supports nasopharyngeal carcinoma cell aggressiveness by inhibit E-cadherin transcription through forming a co-repressor complex with HDAC1/HDAC2 and Snail [13].
    Materials and methods
    Discussion Generally, the development of cancer arise from gene mutations or altered gene expression, which eventually cause dysregulation of numerous important oncogens, tumor suppressor proteins and noncoding RNAs [14]. Chancges in genes expression involved in not only genetic and environmental factors but also epigenetic factors that do not affect the primary DNA sequence [15,16]. Epigenetic alterations of chromatin include DNA methylation or demethylation as well as altered patterns of histone modifications, which can affect gene-expression profiles and contribute to the formation and progression of cancer [[17], [18], [19]]. As an important subunit of PRC2, EZH2 is over-expressed in multiple cancers and silences a lot of tumor suppressor genes transcription [20]. For example, over-expression of EZH2 induced H3K27me3 modification in Ovarian Cancer is associated with epigenetic repression of the ARHI tumor suppressor gene [21]. Moreover, EZH2 dependent H3K27me3 is also involved in epigenetic silencing of ID4 in prostate cancer [22]. These findings indicate that EZH2 plays an important role in cancer development and progression. In this study, we found that EZH2 was significantly over-expressed in gastric cancer tissues and cells, and increased EZH2 expression was correlated with patients shorter overall survival. Moreover, knockdown of EZH2 inhibited gastric cancer cells proliferation and impaired cell migration and invasion in vitro and in vivo. Meanwhile, a lot of previous studies showed that EZH2 can repress many important tumor suppressor genes expression and contribute to cancer cells proliferation and metastasis [[23], [24], [25]]. For example, EZH2 could promote the activation of wnt signaling in gastric carcinogenesis through down-regulation of CXXC4 expression [26]. In the present study, we found that EZH2 involved in gastric cancer cells proliferation partly via regulating P21 expression. P21, a member of the Cip/Kip family of cyclin kinase inhibitors (CKIs), acts as a master effector of multiple tumour suppressor pathways for anti-proliferative activities [27]. In addition, P21 mediates biological activities primarily by binding to and inhibiting the kinase activity of the cyclin-dependent kinases (CDKs), which results in growth arrest at specific stages in the cell cycle [28]. Dysregulated p21 expression often correlates with the loss of p21 transcriptional activators (including p53) and up-regulation or mutations of p21 transcription suppressors. Therefore, the regulation of p21 transcription is complex. A variety of transcription factors, such as p53, activator protein 2, STATs and CCAAT/enhancer binding protein alpha, can regulate P21 transcription in response to different signals [29,30]. In the present study, we found that epigenetic alteration, such as H3K27me3 modification mediated by EZH2 also contributes to transcription repress of P21 in gastric cancer cells.