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 ten-eleven 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 17β-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.

Keywords: DNA methylation; TET proteins; epigenetics; histone modification; leiomyoma; miRNA; oxidative DNA demethylation; stem cells.

Figure 1.

Schematic representation of DNA demethylation pathways. TET proteins can oxidize 5mC to generate 5hmC. 5hmC can also be further oxidized by TET proteins to produce 5fC and 5caC. The above 3 modified C, served as intermediates for DNA demethylation, can be diluted during DNA replication. On the other hand, 5fC and 5caC can be excised from DNA by TDG generating an abasic site as part of the base excision repair process that regenerates unmodified C. DNMT indicates DNA methyltransferase; TET, ten-eleven translocation protein; TDG, thymine DNA glycosylase; C, cytosine; 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; 5fC, formylcytosine; 5caC, 5-carboxylcytosine.

Figure 2.

Schematic representation of epigenetic mechanisms involved in human leiomyoma formation. DNA methylation, histone modifications, and micro RNA (miRNA) play a crucial role in modulating the gene expression pattern in the pathogenesis of leiomyoma. TET1 indicates ten-eleven translocation protein 1; TET3, ten-eleven translocation protein 3; EZH2, enhancer of zeste 2; HDAC, histone deacetylase; Dicer, an enzyme that cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small-interfering RNA and microRNA, respectively; RISC, RNA-induced silencing complex; KLF11, Kruppel-like factor 11; DLEC1, deleted in lung and esophageal cancer 1; DAPK1, death-associated protein kinase 1; KRT19, keratin 19.

Figure 3.

Hierarchy of differentiation of stem cells and specific genetic/epigenetic abnormalities relevant to human leiomyoma formation. Environmental factor-induced genetic/epigenetic abnormalities alter the gene expression pattern and function of undifferentiated stem/transit amplifying (TA) cells leading to the formation of a population of proliferating cells, called tumor-initiating cells (TICs), which differ from the rest and could develop into a uterine leiomyoma. HMGA2 indicates high mobility group AT-Hook 2; RAD51B, RAD51 Paralog B; FH, fumarate hydratase; TSC2, tuberous sclerosis 2; MED12, mediator complex subunit 12.