The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

Abstract

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.

The Emerging Spectrum of Early Life Exposure-Related Inflammation and Epigenetic Therapy

“…These changes do not occur as a result of the alteration in DNA sequencing [26]. DNA methylation and histone modification are the two major epigenetic mechanisms, which collaborate to package genes in euchromatin or heterochromatin, a packaging that determines whether a gene is activated or silenced.…”

Genetic mechanisms of uterine leiomyoma

“…Роль микроРНК была рассмотрена также в рабо-те «Механизм и функции эпигенетики в развитии лейомиомы матки» [6]. Ученые из США попытались доказать, что метилирование ДНК, модификация гистонов и микроРНК, как механизмы эпигенетиче-ской регуляции, вовлечены в сложный процесс аберрантной экспрессии генов, приводящий к трансформации клеток и способствующий развитию многих заболеваний, в том числе и миомы матки.…”

“…Кроме того, он подавляет экспрессию 17β-эстрадиола и прогестерона и активирует мРНК для нескольких коллагенов в ксенотрансплантатах лейомиомы матки. Это исследование показывает, что чрезмерная продукция ECM в лейомиоме матки регулируется с помощью стероидных гормонов по-давлением mir-29b [6].…”

“…Важная роль активного деметили-рования ДНК (превращение 5-метилцитозина (5-MC) в 5-гидроксиметилцитозин (5-HMC) окислени-ем 5-MC, влияющее на активность отдельных генов и воздействующее на структуру хроматина) [18] была недавно идентифицирована в отношении TET protein 1 (TET1) и TET protein 3 (TET3), опосредо-ванная повышенным уровнем 5-гидроксиметилци-тозина (5-hmC) в лейомиоме. Кроме того, гистоны (класс ядерных белков, участвующих в упаковке ни-тей ДНК в ядре и в эпигенетической регуляции таких ядерных процессов, как транскрипция, реплика-ция и репарация) метилтрансферазы и дезацетилазы, согласно этому же исследованию, вовлечены в пато-генез лейомиомы [6…”

Ultrasound guided high-intensity focused ultrasound combined with gonadotropin releasing hormone analogue (GnRHa) ablating uterine leiomyoma with homogeneous hyperintensity on T2 weighted MR imaging

“…Oestrogen plays a role in the development of uterine leiomyoma; 3,4 gonadotropin-releasing hormone analogue (GnRHa) can bind tightly to GnRHa receptor and inhibit female hormone secretion by way of the hypothalamuspituitary-gonad axis. GnRHa is used to treat uterine leiomyoma, as first reported by Filicori, 4 and it has been widely used for a long time since then.…”