Epigenetic Regulation of E-Cadherin Controls Endometrial Receptivity

Rahnama, Fahimeh; Thompson, Bridget; Steiner, Michael; Shafiei, Farhad; Lobie, Peter E.; Mitchell, Murray D.

doi:10.1210/en.2008-1142

Cited by 93 publications

(68 citation statements)

References 59 publications

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“…However, recent studies in endometrial epithelial carcinoma and choriocarcinoma cell lines have shown that the siRNAmediated downregulation of the individual DNMT genes did not cause an increase in E-cadherin expression; however, concurrent knockdowns of DNMT3a and DNMT3b induced E-cadherin expression. Furthermore, E-cadherin expression significantly increased after concomitant knockdown of DNMT1, 3a and 3b (Rahnama et al, 2006(Rahnama et al, , 2009). Here we show that inhibition of p53 leads to an increase in DNMT1 expression and does not alter the expression of DNMT3a or DNMT3b in SBOT cells.…”

Section: Discussionmentioning

confidence: 96%

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

2011

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The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinomaderived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibitioninduced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

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Section: Discussionmentioning

confidence: 96%

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

2011

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“…MET is required for reprogramming from fibroblasts to pluripotent cells [17,38]. The key epithelial gene E-cadherin is critically linked to pluripotency in ES cells and is essential for iPSC generation, and its expression is significantly increased after AZA treatment [17,[39][40][41]. The normal activation of the Dlk1-Dio3 imprinted region is positively correlated with the developmental potential of iPSCs [18,19].…”

Section: Discussionmentioning

confidence: 99%

microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

Guo¹,

Liu

Wang

et al. 2012

Cell Res

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Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM-and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.

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“…It has been shown that endometrial receptivity could be modulated by a multitude of signaling molecules, including prostaglandins [3], growth factors, cytokines, chemokines, integrins, leukemia inhibitory factor [4,5], Wnt family ligands [6], and E-cadherin [7]. Whereas dysregulation of some of these factors could be associated with repeated implantation failure, key molecular mechanisms that underlie the regulation of endometrial receptivity remain to be elucidated [8].…”

Section: Introductionmentioning

confidence: 99%

Site-specific endometrial injury improves implantation and pregnancy in patients with repeated implantation failures

Huang

Wang

Soong

et al. 2011

Reprod Biol Endocrinol

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BackgroundTo test whether a site-specific hysteroscopic biopsy-induced injury in the endometrium during the controlled ovarian hyperstimulation cycle improves subsequent embryo implantation in patients with repeated implantation failure, a total of 30 patients who have had good responses to controlled ovulation stimulation but have failed to achieve pregnancy after two or more transfers of good-quality embryos were recruited in this prospective study.MethodsA single, site-specific hysteroscopic biopsy-induced injury was generated on the posterior endometrium at midline 10-15 mm from the fundus during the D4-D7 period of the ongoing controlled ovarian hyperstimulation cycle in six patients.ResultsPatients received endometrial biopsy protocol achieved a pregnancy rate of 100%. By contrast, only 46% of patients with similar clinical characteristics (N = 24) achieved pregnancy without the hysteroscopic biopsy-induced endometrium injury (p < 0.05).ConclusionsOur proof-of-concept study demonstrates that a site-specific hysteroscopic endometrium injury performed during the ongoing in vitro fertilization (IVF) cycle, instead of injuries received during prior cycles, significantly improves clinical outcomes in patients with repeated implantation failure.

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Epigenetic Regulation of E-Cadherin Controls Endometrial Receptivity

Cited by 93 publications

References 59 publications

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming

Site-specific endometrial injury improves implantation and pregnancy in patients with repeated implantation failures

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