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  • Enhancer of zeste homolog EZH

    2022-06-30

    Enhancer of zeste homolog 2 (EZH2), which functions as a methyltransferase, is a critical subunit of polycomb repressive complex 2 (PRC2), which has been demonstrated to be involved in the development of the pkg inhibitor [23]. Aberrant expression of EZH2 has been found to be associated with a variety of human cancers due to the gene suppressing activity of EZH2 [24,25]. An increasing number of studies have revealed that miRNAs may produce oncogenic or anti-oncogenic effects by regulating the expression of EZH2 [[26], [27], [28]]. For instance, Cui S et al have reported that miR-137 can inhibit tumor growth of liver cancer by downregulating EZH2 expression [26]. However, whether EZH2 plays a role in the hsa_circ_0071589/miR-600 regulatory axis in colorectal cancer remains undetermined. In this present study, bioinformatics analysis and luciferase reporter assay revealed that miR-600 is able to bind to EZH2, and we found that the downregulation of EZH2 caused by hsa_circ_0071589 knockdown in the CRC cell line could be reversed by anti-miR-600. Further functional experimental results also suggested that the tumor inhibitory effects of hsa_circ_0071589 silencing in the CRC cell line could be abolished by anti-miR-600.
    Conflict of interest
    Introduction Anteroposterior pattern of the vertebrate limb is established in the lateral plate prior to limb initiation (Hamburger, 1938; Chaube, 1959). During early stages of limb development that precede the establishment of the zone of polarising activity (ZPA) and the apical ectodermal ridge (AER), mutual antagonism between anterior Gli3 and posterior Hand2 functionally polarises the limb bud (Panman and Zeller, 2003; te Welscher et al., 2002a; Galli et al., 2010). Although sonic hedgehog (Shh) is not yet expressed at that prepatterning stage, repression of the hedgehog pathway by Gli3 is nonetheless essential to perpetuate anterior identity (Li et al., 2014; Zhulyn et al., 2014; Tao et al., 2017). Once the ZPA is established, graded anterior repression of Shh targets by Gli3 has been proposed to confer distinct morphology to skeletal elements along the anteroposterior axis (Wang et al., 2000; Pan et al., 2009; te Welscher et al., 2002b; Towers et al., 2012; Zhu et al., 2008). The hedgehog pathway contributes to pattern, in part, by regulating downstream 5′ Hox genes (Zakany et al., 2004; Panman et al., 2006) that modulate a basal reaction-diffusion mechanism (Sheth et al., 2012). The repressive function of Gli3 is essential to pattern the anterior limb. In mammals, the GLI transcription factor family has three members. GLI proteins are capable of acting as activators in the presence of hedgehog ligand or repressors in the absence of ligand. Although both GLI2 and GLI3 are capable of both activator and repressor functions, GLI2 is the predominant activator whereas GLI3 is the main repressor of hedgehog signalling in the limb (Hui and Angers, 2011; Jiang and Hui, 2008). Gli1 is a direct target of hedgehog signalling that serves to reinforce GLI activator function. In the absence of hedgehog ligand, the full length active form of GLI undergoes protein kinase A-mediated phosphorylation that targets the protein for cleavage, thereby rendering it a repressor (Wang et al., 2000; Pan et al., 2009). Although truncated GLI3 is important in the limb, it is unclear whether its repressor function is mediated by other regulators. Among differentiating cells, progenitor genes are typically silenced as chromatin becomes labelled with repressive epigenetic marks (Laugesen and Helin, 2014). Polycomb repressive complexes 1 and 2 (PRC1/2) contribute to gene silencing during development and regeneration, including that of the limb (Yakushiji-Kaminatsui et al., 2016; van der Velden et al., 2012; Hamada et al., 2015; Stewart et al., 2009; Wyngaarden et al., 2011). Multiple histone marks are associated with gene repression, including trimethylation of lysines 9 and 27 of histone H3 by PRC2. The enzymatically active subunit of PRC2 is the SET domain protein enhancer of zeste 2 (EZH2) (Cao et al., 2002; Czermin et al., 2002; Kuzmichev et al., 2002; Muller et al., 2002) that is essential for limb pattern (Wyngaarden et al., 2011). In the limb bud, loss of Ezh2 results in ectopic anterior expression of the Shh target genes Ptch1 and Gli1 in the absence of ectopic expression of Shh ligand. These changes are accompanied by other expression changes that reflect posteriorised identity of the anterior limb bud (Wyngaarden et al., 2011). Since Gli3 itself is diminished but not eliminated in conditional Ezh2 mutants, it is unclear whether anterior repression of posterior identity is normally regulated independently by these two regulators, or whether they are codependent to some extent.