Potential Mechanisms of Aberrant DNA Hypomethylation on the X Chromosome in          Uterine Leiomyomas

Sato, Shun; Maekawa, Ryo; Yamagata, Yuriko; Asada, Hiromi; Tamura, Isao; LEE, Lifa; Okada, Maki; Tamura, Hiroshi; Sugino, Norihiro

doi:10.1262/jrd.2013-095

Cited by 30 publications

(20 citation statements)

References 41 publications

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“…However, the expression of TSPYL2 was not upregulated in leiomyoma samples. 78 Leiomyomas are estrogen-dependent tumors. A growing body of evidence within the literature has investigated a link between the ER signaling and epigenetic regulation.…”

Section: Dna Methylation In Uterine Leiomyomamentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

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Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and teneleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17b-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.

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Section: Dna Methylation In Uterine Leiomyomamentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

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“…Remarkably, when the same regions were analysed on the samples of endometrial diseases, there were observed discrepancies, because the levels of methylation of these promoter regions did not correlate with the lack of ERα protein in human patient samples with endometrial disease. 89 Furthermore, in the study by Sato et al, 90 an aberrant hypomethylation within sequences of X chromosome including TSPYL2 gene has also been demonstrated. These changes were connected to higher expression of this gene in normal myometrium, whereas expression was not upregulated in case of leiomyomas.…”

Section: Epigenetic Background Of Tumourigenesis Of Leiomyomasmentioning

confidence: 92%

Molecular and clinical attributes of uterine leiomyomas

et al. 2017

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Uterine leiomyomas, also called uterine fibroids or myomas, represent one of the most common benign tumour types in women of a fertile age. Leiomyomas arise due to transformation of the layer of smooth muscle cells of corpus uteri - the myometrium. Despite frequent occurrence of this disease, the molecular mechanisms behind the origin and development of leiomyomas are still relatively unknown. Most predisposed are obese women and women of African origin. In more than half of cases, leiomyomas remain asymptomatic. Genetic factors also have an important impact on the development of these hormone-dependent tumours. However, the clinical and molecular characteristics of familiar and sporadic leiomyomas can widely differ. The main reason is the heterogeneity of this disease and the abundance of factors which can underlie their tumourigenesis. Clinical diagnosis of uterine leiomyomas without surgical interference can be hindered in the case of small, mostly submucosal leiomyomas or if it is necessary to avoid potential malignancy of tumour. Also, medical treatment of uterine leiomyomas cannot be nowadays considered sufficient with many medical agents still being tested only within clinical research. The main goal of this article is to summarise known facts about the aetiology of leiomyomas, risk factors that contribute to their development, known molecular-genetic aberrations connected with the presence of leiomyomas as well as the possibilities of their diagnosis and treatment.

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“…Bisulfite reactions were performed using an EpiTect Bisulfite Kit (Qiagen) with the following temperature conditions: 95 °C for 5 min, 65 °C for 85 min, 95 °C for 5 min and 65 °C for 175 min as previously reported [38]. The bisulfite-converted DNA was amplified by PCR using the primer pairs for ESR1 and ESR2 shown in Table 2 using the following thermocycling conditions: 95 °C for 10 min, and 40 cycles of 94 °C for 30 s, 60 °C for 30 s and 72 °C for 1 min followed by 10 min of final extension at 72 °C.…”

Section: Methodsmentioning

confidence: 99%

Aberrant DNA methylation suppresses expression of estrogen receptor 1 (ESR1) in ovarian endometrioma

et al. 2019

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BackgroundIn ovarian endometriomas (OE), the expression statuses of various steroid hormone receptors are altered compared with their expression statuses in eutopic endometrium (EE). For example, in OE, the expressions of estrogen receptor 1 (ESR1), which encodes ERα, and progesterone receptor (PGR) are downregulated, while the expression of ESR2, which encodes ERβ, is upregulated. The causes of these changes are unclear. DNA methylation of a specific region of a gene can result in tissue-specific gene expression. Such regions are called tissue-dependent and differentially methylated regions (T-DMRs). We previously reported that the tissue-specific expression of ESR1 is regulated by DNA methylation of a T-DMR in normal tissues. In the present study, we examined whether aberrant DNA methylation of the T-DMR is associated with the altered expressions of ESR1, ESR2 and PGR in OE.ResultsGene expression levels of ESR1, ESR2 and PGR were measured by quantitative RT-PCR. The expression levels of ESR1 and PGR were significantly lower and the expression level of ESR2 was significantly higher in OE than in EE. DNA methylation statuses were examined with an Infinium HumanMethylation450K BeadChip and sodium bisulfite sequencing. DNA methylation at the T-DMRs of ESR1 were significantly higher in OE than in EE, but no significant differences were observed in the DNA methylation statuses of ESR2 and PGR.ConclusionsAberrant DNA methylation of the T-DMR was associated with the impaired expression of ESR1, but not the altered expressions of ESR2 and PGR, in OE.

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Potential Mechanisms of Aberrant DNA Hypomethylation on the X Chromosome in Uterine Leiomyomas

Cited by 30 publications

References 41 publications

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

Molecular and clinical attributes of uterine leiomyomas

Aberrant DNA methylation suppresses expression of estrogen receptor 1 (ESR1) in ovarian endometrioma

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