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  • calcifediol Here we employ a genetic approach to examine the

    2022-01-14

    Here we employ a genetic approach to examine the potential interaction of Gli3 and Ezh2 with respect to anteroposterior limb bud polarity. Loss of Ezh2 in a Gli3 mutant background leads to synergistic loss of anterior identity, although the double mutant phenotype more closely resembles that of Ezh2 than Gli3 single mutants. Neither removal of Gli activator nor overexpression of a constitutive Gli repressor is sufficient to rescue the posteriorised mutant Ezh2 limb bud phenotype. The data suggest Ezh2 is epistatic to Gli3, raising the possibility that it mediates repression of hedgehog signalling in the anterior limb bud.
    Results
    Discussion
    Materials and methods
    Declaration of interest
    Acknowledgements This study was funded by the Canadian Institutes of Health Research (MOP 137092).
    Introduction Curcumol is the main active ingredient in Rhizoma Curcuma, a common traditional Chinese medicine (TCM). It is reported to possess antitumor [[1], [2], [3], [4], [5], [6], [7], [8]] and anti-inflammatory properties [9], but little is known about the molecular mechanism underlying these effects. Recent studies have attempted to investigate the antitumor activity of curcumol in various types of cancers, including lung cancer [1], esophageal carcinoma [3], colorectal cancer [7], breast cancer [8]and nasopharyngeal carcinoma [10]. These studies indicate that the p38 MAPK [7] and NF-kappaB [8]signaling pathways are involved in the antitumor effects of curcumol. Enhancer of zeste homolog 2 (EZH2) is a member of the Polycomb-group (PcG) family [11]. PcG family members form multimeric protein complexes that are involved in maintaining the transcriptional repression of genes over successive cell generations. EZH2 associates with the embryonic calcifediol development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. EZH2 may play a role in the hematopoietic and central nervous systems. Recent research has demonstrated that EZH2 plays an important role in tumorigenesis, metastasis and invasion. Targeting EZH2 is now considered to be a therapeutic strategy in cancer [12], and EZH2 inhibitors are showing early signs of promise in clinical trials.
    Materials and methods
    Western blot analysis
    Statistical analysis Data are shown as the mean ± SD unless otherwise noted. Student’s t-test was used to analyze the difference between two groups. A P value <0.05 was considered statistically significant.
    Results
    Discussion Previous studies have demonstrated that curcumol induces cell death in various types of cells, including hepatic stellate cells [4], lung cancer cells [1,6] and colorectal cancer cells [7]. The molecular mechanism underlying the inhibitory effects of curcumol on different cells involves different signaling pathways. Curcumol induces cell death in HSC-T6 cells through the PI3K and NF-kappaB pathways [4] and in colorectal cancer cells through the IGF-1R and p38 MAPK pathway [7]. The inhibitory effects of curcumol on lung cancer cells involve the caspase-independent mitochondrial pathway [1]. In a previous study, we found that curcumol induces cell death in bladder cancer cells. However, the mechanism is not clear yet. The MMP is important to maintain mitochondrial oxidative phosphorylation and produce adenosine triphosphate [13].The stability of the MMP assists in maintaining the normal physiological function of cells [14,15]. Accumulating evidence indicates that apoptosis is often accompanied by a loss of the MMP [16].Mitochondrial membrane potential loss is a signature of intrinsic apoptosis. ROS is one of the contributing factors to MMP loss [15,17].We found that forced expression of EZH2 alleviates curcumol-induced ROS generation and MMP loss. Conversely, silencing EZH2 enhances these cucumol-induced effects. These data suggest that EZH2 modulates curcumol-induced apoptosis through ROS generation and MMP loss. We further investigated the effects of EZH2 on key members of the mitochondrial apoptosis pathway. Intrinsic control of apoptosis requires activation of cytosolic caspases by the release of mitochondrial cytochrome c and involves permeabilizationof the mitochondrial outer membrane as controlled by the Bcl-2 family of proteins [18]. Bcl-2 proteins that promote cell death include those containing either multiple BH domains (i.e., Bax, Bak) or a single BH3 sequence (Bad, Bik, Bid, Puma, Bim, Bmf, and Noxa) [18,19]. Pro-survival, multi-BH domain Bcl-2 proteins include Bcl-2, Bcl-xL, and Bcl-w [19]. Pro-apoptotic Bax and Bakoligomerize at the mitochondria to alter membrane permeability and allow cytochrome c release into the cytosol [20,21].Our data demonstrated that EZH2 increases accumulation of Bcl-2 and decreases expression of Bax, Bak and cytochrome c in EJ and T24 cells exposed to curcumol. These results indicate that EZH2 may function as an inhibitor of the mitochondrial apoptosis pathway during curcumol-induced apoptosis.