Epigenetic Modifications and Carcinogenesis of Human Endometrial Cancer

Review Article

Austin J Clin Pathol. 2014;1(3): 1014.

Epigenetic Modifications and Carcinogenesis of Human Endometrial Cancer

Xianyong Ma*, Xiaobin Gao

Department of Pathology, Yale University School of Medicine, USA

*Corresponding author: Xianyong Ma, Department of Pathology, Yale University School of Medicine, New Haven, USA

Received: July 02, 2014; Accepted: Aug 01, 2014; Published: Aug 04, 2014


The endometrial cancers (EC) or uterine cancers (UC), which arise from endometrium of uterus, are the seventh most common malignancies worldwide among females. According to the estimation from NCI, there will be around 52,630 new cases and 8,590 deaths from EC in USA in 2014 [1], therefore the exploration of the mechanisms for EC carcinogenesis and development for cost-effective treatment approaches are important and urgent. The significance of genetic alterations (changes DNA sequences) have been extensively explored in carcinogenesis of human endometrial cancer [2,3], but these studies do not provide a reasonable explanation of why the gene sequences are not changed in many endometrial cancer cases. Increasing evidence from recent research shows that the epigenetic regulation for gene expression is critical for endometrial carcinogenesis [4,5]. The epigenetic modifications do not change DNA sequences, but alter the side chain groups of DNA base or histone proteins, and then regulate gene expression to affect the biological function of cells. The epigenetic modifications can be structurally classified as following: 1. DNA methylations/demethylations; 2, Histone methylations/ demethylations; 3, Histone acetylations/deacetylations; 4, Histone phosphorelations/dephosphorelations; 5, other modifications such as deimination in DNA; β-N-acetylglucosamine, ADP ribosylation and Ubiquitylation/sumoylation in histones, also including histone tail clipping and histone proline isomerization. In addition, the concept of epigenetic regulation has been extended to microRNAs (miRNA) and LncRNA regulations, since these RNA molecules regulate the gene expression by partially match to target (complementary RNA strand) mRNA and then lead to inhibition and/or mRNA degradation. In this paper we review the impact of epigenetic modifications and related biological implications in carcinogenesis of human endometrial cancer, and also discuss possible treatment strategies based on the epigenetic alterations.

DNA Modifications in EC Carcinogenesis

In mammalian cells, DNA methylation/demethylation is one of the most popular epigenetic modifications and play fundamental role in regulation of gene expression.

The methylation status of promoter region determines if gene activation or inactivation, also control gene expression level. Abnormal DNA methylation patters (higher or lower than normal methylation level) have been associated with human tumors, as well as other neoplastic diseases [6].

Hypermethylation of tumor suppressor genes in EC carcinogenesis

The DNA methylation is catalyzed by DNA methyltransferases, which consist of three members of DNMT1, DNMT3A and DNMT3B. DNMT1 is the most abundant DNA methyltransferase among these enzymes. DNMT1 catalyzes the methylation of the 5'-cytosine in the CpG dinucleotide sequence, and plays an important role in maintaining the DNA methylation patterns during cell division [7]. The DNMT3A/3B catalyzes de novo methylation of DNA [8]. These three enzymes cooperatively catalyze the methylation reactions of CpG islands, which are often located in promoter regions of target genes [9]. Hypermethylation means the methylation exceeds physiological level of target DNAs (Figure 1), the hypermethylation of promoters leads to inactivate the expression of tumor suppressor genes and loss of corresponding proteins to repress carcinogenesis, thereby promoting carcinogenesis and enhancing the metastases of cancer cells. A number of tumor suppressor genes have been determined with frequent hypermethylation on promoter regions during endometrial carcinogenesis (See Table 1). The development of new assay methods for DNA methylation such as MLPA (methylation-specific multiplex ligation-dependent probe amplification)[10], Mass ARRAY analysis [11], MethylCap-Seq [12] supplies the possible tools to globally screen the methylations of tumor samples. MethylCap- Seq is based on the affinity purification of methylated CpG of DNA fragments by using tagged methylation binding protein MeCP2, and then sequencing the purified DNA fragments to understand the methylation status of DNA. Jones A et al. [13] carried out a global-scale hypermethylation assay to screen more than 27,000 CpG sites (from 64 endometrial cancers and 23 control samples), they found HAND2, which expresses in normal endometrium, is one of the most frequently hypermethylated and silenced genes in endometrial cancer cells. The global profiling for promoter methylation was also successfully used to find out hypermethylation statuses of tumor suppressor genes such as MLH1 [14], Tig, C/EBPα [15], PRs, ERs [16], microRNAs [17]. The assays for individual tumor suppressor genes have also been used to determine a number of genes that are repressed in endometrial cancer by hypermethylation of promoter regions, for example, the PTEN, a critical factor regulating PI3K-AKT pathway, has been detected with frequent mutations, deletion and promoter hypomethylation in EC [18], studies also showed that loss of PTEN expression due to promoter hypermethylation associated with MSI (Microsatellite instability) phenotype [19]. P16INK4a or CDKN2A, an inhibitor of cyclin-dependent kinases such as CDK4 and CDK6, plays as tumor suppressor in EC carcinogenesis, the promoter hypermethylation of P16INK4a gene has been reported in between 11% to 75% sporadic endometrial cancer [20-23]. Other tumor suppressor genes frequently detected with promoter hypermethylation in EC by similar procedures include RASSF1A (Ras associated domain gene family) (33%-85%) [24-25]; APC (Adenomatous polyposis coli) up to 46.6%) [26]; RUNX3 (86%) [27]; CDH13 (cadherin 13) (90%) [28]; E-cadherin (79.8%) [29]. In addition to these tumor suppressor genes, some potential tumor suppressor genes were also frequently detected: for example: 14-3-3s gene was hypermethylated in 40%-60% endometrial cancer and ovary cancer [30] (see Table 1 for detailed gene list).