Heparin sale CDX is also a tumor suppressor gene the ablatio

CDX1 is also a tumor suppressor gene; the ablation of CDX1 and CDX2 results in a significant increase in tumor formation in the colon. CDX1 is regulated by epigenetic modification; the hypermethylation of the CpG island at the promoter is positively associated with severe clinical phenotypes. In addition, it is one of the EMT-related genes. CDX1 or CDX2 expression enhances E-cadherin-mediated cell-cell adhesion in human COLO 205 cells.27, 45 In our study, we found there exists a physical association between EZH2 and H3K27me3 at the CDX1 promoter in trophoblast Heparin sale by ChIP-qPCR. Furthermore, CDX1 promoter activity significantly diminished after the overexpression of EZH2, indicating the methylation of H3-K27 by EZH2 at the CDX1 promoter and consequent suppression of CDX1. Moreover, the expression of CDX1 increased in the villous tissues of RM patients, which was opposite to the EZH2 expression. In addition, our study also showed that enhanced CDX1 expression inhibited invasion of trophoblast, upregulated E-cadherin, and downregulated N-cadherin, which means that the CDX1 expression inhibited EMT. Overall, we speculate that EZH2 could promote trophoblast invasion via the indirect promotion of EMT by inhibiting the CDX1 expression. The PI3K/AKT and ERK1/2 signaling pathways are both verified to be involved in the progress of cellular growth, proliferation, and invasion. Whereas EZH2 expression is regulated by the AKT and ERK1/2 pathways, phos (p)-AKT and p-ERK1/2 proteins are less expressed in the RM group compared with the control group. In addition, previous research has reported that trophoblast invasion and migration could be promoted by progesterone, which is widely used in clinical practice.28, 47, 48 Furthermore, Pal et al. found that the expression and phosphorylation of EZH2 (Thr487) coincide with H3K27me3 modification and peak during pregnancy, which is driven by progesterone. Therefore, we examined p-AKT and p-ERK1/2 expression after progesterone treatment. Our work indicated that progesterone could activate the ERK1/2 pathway and, thus, significantly increase the expression of EZH2 accompanied with the decreased level of CDX1, but not the PI3K/AKT signaling pathway. This is in accordance with the results that report that progesterone is able to induce phosphorylation of ERK1/2 in two choriocarcinoma cell lines (BeWo and JEG-3) and is consistent with the reports demonstrating that the phosphorylation of EZH2 at serine 21 suppresses its methyltransferase activity responsible for H3-K27 trimethylation.50, 51 The decreased expression of EZH2 in women with RM provides new insights into the epigenetic mechanisms underlying the pathogenesis of RM and paves new avenues for the development of novel therapeutics.
Materials and Methods
Author Contributions
Conflicts of Interest
Acknowledgments The authors would like to thank all of the RM patients for their participation during this study. This work was supported by the Major Program of the National Natural Science Foundation of China (grant 81490743 to Z.-J.C.), National Key R&D Program of China (grant 2017YFC1001403), National Natural Science Foundation of China (NSFC; grants 31671199 and 31871512 to C.Z.), and Shanghai Commission of Science and Technology (grant 17DZ2271100).
Introduction Prostate cancer (PCa) is the most frequently diagnosed cancer and the third most frequent cause of cancer deaths in United States males (Siegel et al., 2015). PCa patients have benefitted from androgen deprivation therapies (ADTs) and small molecular inhibitors targeting the androgen receptor (AR). However, 30% of patients have primary resistance to both forms of treatment, and the majority of patients progress from androgen-dependent PCa (ADPC) to castration-resistant PCa (CRPC). The AR remains a key driver of CRPC through aberrant activation in the milieu of low androgen. Enhancer of Zeste 2 (EZH2) is a bona fide oncogene that is among the most highly upregulated genes in CRPC relative to localized PCa (Varambally et al., 2002). EZH2 is a core subunit of the Polycomb Repressive Complex 2 (PRC2), which also contains embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12). EZH2 is the catalytic member of PRC2 and contains a C-terminal su(var)3-9, enhancer-of-zeste and trithorax (SET) domain that specifically catalyzes histone H3 lysine 27 trimethylation (H3K27me3), leading to epigenetic (defined as histone modifications) silencing of many tumor suppressor genes (Yu et al., 2010, Zhao et al., 2012).