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

Introduction

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).

Figure 1:

DNA Methylation/Demethylation and Epigenetic Treatment of Cancers.

The DNA methylation/demethylation reactions catalyzed by DNA methyltransferase (DNMT) and demethylase (DNDME) respectively control DNA methylation status in cells. The hypermethylations of tumor suppressor gene promoters are very common epigenetic alterations and play critical role in endometrial carcinogenesis. The hypermethylation of DNA can be biochemically corrected by DNA methyltransferase inhibitors (DNMTi), therefore recovery the normal methylation status of tumor suppressor gene promoters and reactivate the expression of these genes to eventually overcome the malignant phenotype of cancer cells. Similarly, the DNA demethylase inhibitors (DNDMEi) inhibit the demethylation and inactivate these oncogenes in epigenetic treatment of EC and other cancers.






Figure 1:  
DNA Methylation/Demethylation and Epigenetic Treatment of Cancers.


The DNA methylation/demethylation reactions catalyzed by DNA methyltransferase (DNMT) and demethylase (DNDME) respectively control DNA methylation status in cells. The hypermethylations of tumor suppressor gene promoters are very common epigenetic alterations and play critical role in endometrial carcinogenesis. The hypermethylation of DNA can be biochemically corrected by DNA methyltransferase inhibitors (DNMTi), therefore recovery the normal methylation status of tumor suppressor gene promoters and reactivate the expression of these genes to eventually overcome the malignant phenotype of cancer cells. Similarly, the DNA demethylase inhibitors (DNDMEi) inhibit the demethylation and inactivate these oncogenes in epigenetic treatment of EC and other cancers.

Table 1: Hypermethylation Genes in Endometrial Carcinogenesis.




  

    
Target Genes (Proteins) 

      
 

    
Functions of Target Proteins 

    
Hypermethyla-tion Locations 

    
Regulation of Expression

    
Tumor Type

    
Reference 

  

  

    
14-3-3    sigma

      
APC

      
AR

      
C/EBPa

      
CASP8

      
CDH1/E-cadherin

      
CDH13

      
CDKN2A/P16,

      
CHFR

      
CIDEA

      
COMT

      
EFEMP1

      
ERa

      
FHIT

      
GATA5

      
GSTP1

      
HAAO

      
HAND2

      
HOPX

      
MGMT

      
MiR129-2

      
MiR130a/b

      
MiR152

      
Mir196b

      
MiR200b

      
MiR203

      
miR222

      
MiR34b

      
MiR625

      
MLH1

      
MSH2

      
MT-1E

      
OX2R

      
P14-ARF

      
P73

      
Par-4

      
PEG3

      
PR

      
PR-B

      
PTEN

      
RAR-beta2

      
RASSF1A

      
RSK4

      
RXFP3

      
SFRP1

      
SPARC

      
Sprouty    2

      
TIG

      
TIMP3

      
TSLC1

      
VHL

      
WT1

      
ZNF154 

    
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor **

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor

      
Tumor    Suppressor P*

    
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
1st Exon

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
1stExon/1stIntron

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

    
Downregulation

      
Downregulation

      
Inactivation

      
Downregulation

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

      
Downregulation MSI

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

      
Downregulation MSI

      
Inactivation

      
Inactivation

      
Downregulation

      
Inactivation, MSI

      
Inactivation, MSI

      
Inactivation

      
Downregulation

      
Inactivation

      
Inactivation

      
Inactivation

      
Downregulation

      
Inactivation

      
Inactivation, MSI

      
Inactivation

      
Downregulation

      
Inactive

      
Inactivation

      
Downregulation

      
Downregulation, MSI

      
Inactivation

      
Inactivation

      
Inactivated

      
Inactivation, MSI

      
Downregulation

      
Inactivation

      
Inactivation

      
Downregulation MSI

      
Inactivation

      
Downregulation

      
Downregulation

      
Downregulation

      
Downregulation

      
Inactivation

      
Inactivation

      
Inactivation

      
Inactivation

    
EC, OC

      
EC

      
EC

      
EC

      
EC, OC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
ESC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC, CC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC, OC

      
EC, OC

      
EC

      
EC, OC

    
(30)

      
(21)

      
(67)

      
(15)

      
(68)

      
(24)

      
(28)

      
(20)

      
(69)

      
(73)

      
(70)

      
(71)

      
(16)

      
(29)

      
(72)

      
(24)

      
(73)

      
(13)

      
(74)

      
(75)

      
(72)

      
(77)

      
(77)

      
(17)

      
(77)

      
(77)

      
(77)

      
(78)

      
(77)

      
(77)

      
(79)

      
(80)

      
(81)

      
(82)

      
(83)

      
(84)

      
(85)

      
(86)

      
(87)

      
(19)

      
(88)

      
(24)

      
(89)

      
(73)

      
(86)

      
(90)

      
(89)

      
(15)

      
(91)

      
(92)

      
(68)

      
(94)

      
(68) 

  









Table 1: Hypermethylation Genes in Endometrial Carcinogenesis.

Some members within same family can play bidirectional roles in endometrial carcinogenesis, for example: Homeobox (HOX) genes encode a group of homeodomain-containing transcription factors. Hox family genes have been identified as both tumor suppressor genes and oncogenes in carcinogenesis [31-33]. Some HOX members have been associated with endometrial cancer, Zhao et al. [34] reported that the HOXB13 was upregulated in endometrial cancer and possibly enhanced the invasiveness, which acts as an oncogenic protein in EC carcinogenesis, however, most of HOX family members act as tumor suppressors in EC carcinogenesis, for example, hypermethylation of Hoxa10 and Hoxa11 promoters are positively correlated with endometrial cancer types [35,36].

Hypomethylation of oncogenes in endometrial carcinogenesis

Similar with hypermethylation, the promoter hypomethylation (demethylation) is also a dynamic process presented in mammalian cells. In fact, during carcinogenesis, the DNA methylation pattern has paradoxical alteration: global DNA hypomethylation (demethylation) and local hypermethylation of certain genes. With almost all of the attention on the epigenetic modifications of DNA is focused on the promoter hypermethylations of tumor suppressor genes, very few publications have described the demethylation or hypomethylation in carcinogenesis for all cancers. Nonetheless, hypomethylation of oncogenes also play an important role in carcinogenesis as hypermethylation of tumor suppressor genes do.

In endometrial cancer, the hypomethylation of oncogenes is associated with early stage of carcinogenesis of endometrium through enhancing the ability of cell proliferation. Recently Erling et al. [37] reported CTCFL/BORIS gene (paralogue of CTCF-like factor, brother of the regulator of imprinted site) was hypomethylated on the promoter region and overexpression of this gene was significantly associated with endometrial tumorigenesis and poor survival of patients. Interestingly hypomethylations were also associated with the subtype of endometrial cancer, Hsu et al. [38] reported that bone morphogenetic protein members, BMP2, 3, 4, and 7, which were usually methylated in primary endometrial tumors with nonrecurrent type, but hypomethylated in primary endometrial tumors with the subsequent recurrent type, therefore the methylation patterns of BMP genes can be considered as the biomarkers of poor survival in endometrial cancer treatment. Some non-coding DNA sequences, such as the long interspersed element (LINE, the retrotransposons) [39], are hypomethylated in endometrial cancer, colorectal cancer and gastric cancer, and the hypomethylation of LINE-1 is also a putative biomarker for diagnosis of these cancers, however whether or not this gene directly acts as an oncogene during endometrial carcinogenesis remains unknown. The genes hypomethylated in endometrial cancer are listed in Table 2.

Table 2: Hypomethylation Genes in Endometrial Carcinogenesis.




  

    
Target Genes (Proteins)

    
Functions of Target Proteins

    
Hypomethylation Locations

    
Regulation of Expression

    
Tumor Type

    
Reference

  

  

    
BMP    2,3,4,7

      
CASP8

      
CTCFL/BORIS

      
HOXB13

      
LICAM

      
LINE-1    **

      
MMP-2

      
PARP1

      
PAX2

      
S100A4 

    
Oncogene

      
Oncogene-P*

      
Oncogene-P*

      
Oncogene-P*

      
Oncogene

      
Oncogene-P*

      
Oncogene-P*

      
Oncogene-P*

      
Oncogene

      
Oncogene 

    
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Promoter

      
Whole gene sequence

      
Promoter

      
Promoter

      
Promoter

      
1stIntron 

    
Activation

      
Activation

      
Activation

      
Upregulation

      
Activation

      
Upregulation

      
Upregulation

      
Upregulation

      
Activation

      
Activation 

    
EC

      
EC, OC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

      
EC

    
(38)

      
(68)

      
(37)

      
(34)

      
(95)

      
(39)

      
(96)

      
(97)

      
(98)

      
(99) 

  









Table 2:  Hypomethylation Genes in Endometrial Carcinogenesis.

Histone modifications in EC carcinogenesis

Histones are proteins that the DNA wraps itself to form chromatin. Tails of histone proteins are extensively modified post translationally in normal eukaryotic cells to maintain the functional structure of chromatin. Cancer cells frequently harbor aberrations in histones. Locus-specific alterations in histone modifications may have direct effects on expression of nearby genes. Moreover cancer cells also exhibit alterations in global level modifications, among these epigenetic modifications in histones, the acetylations/ deacetylations and methylations/ demethylations are the major histone modifications that have been reported to play a crucial role in carcinogenesis of EC.

Histone methylation and endometrial cancer

Methylations are one of the most frequent epigenetic modifications on core histones; the histone methylation is mediated by histone methyltransferase (HMT), which contain SET domain to catalyze the reaction of transferring methyl group from donor such as S-adenosyl methionine onto lysine or arginine residues of the H3 and H4 histones. The HMTs can be classified into two groups, group 1 (such as EZH2, Enhancer of Zeste Homolog 2) [40]) HMTs transfer methyl group to lysine residues of histone, group2 (such as PRMT, Protein Arginine Methyltransferase) HMTs transfer methyl group to arginine residues of H3 and H4 histones [41]. After the determination of biochemical function of chromatin repress complex (PRC2), whose core components include EZH2, EED and SUZ12. More and more researchers are focused on the study of EZH2 and PRC2, which transfers methyl group to lysine 27 and 9 residues of H3 [42]. Generally, the EZH2 acts as an oncoprotein during carcinogenesis, Yang et al. [43] found the EZH2 was upregulated in endometrial cancer resulting in hypermethylation of histone 3 lysine 27 of APC promoter, subsequently inactivated the expression of APC tumor suppressor. Zhou et al. [44] also reported that EZH2 was overexpressed in high-grade endometrial tumors. Therefore, the EZH2 was considered to play an oncogenic role in endometrial carcinogenesis by inhibition of tumor suppressor gene expression, even though the PRC2 complex is generally considered as a tumor suppressor complex. Due to the fact that PRC2 (with EZH2) can inactivate both oncogenes and tumor suppressor genes by methylation of histones, in the future, more mechanistic experiments need to be carried out to clarify the relationship of EZH2 oncogenic role and PRC2 tumor suppressor function.

Histone acetylation/deacetylation and endometrial cancer

Histone acetylation and deacetylation reactions, which are the important post-translational modifications involve in regulations of gene expression. Histone acetyltransferase (HAT) catalyzes histone acetylation by transfer acetyl group from the substrate acetyl-coenzyme A to histone, on the other hand, histone deacetylase (HDAC) catalyzes histone deacetylation by removing acetyl group from histone proteins via hydrolysis reaction (Figure 2). In the past years, a number of publications described the HAC activates the gene expression and HDAC acts the opposite, and both procedures play important roles in EC carcinogenesis [45,46].

Figure 2:

Histone Acetylation/Deacetylation and Epigenetic Treatment of Cancers.

The frequent aberrant histone modifications include hypoacetylations on tumor suppressor gene regions or hyperacetylations on oncogene regions in endometrial carcinogenesis. These procedures can be biochemically corrected by enzymatic inhibitors. The histone deacetylase inhibitor (HDACi) can inhibit the deacetylation and reactivation of tumor suppressor genes. Similarly, the acetyltransferase inhibitor (HACi) can inhibit the acetylation and inactivation of oncogenes, therefore, these inhibitors are considered to be as the drugs for EC or other cancer treatment.






Figure 2:  
Histone Acetylation/Deacetylation and Epigenetic Treatment of Cancers.


The frequent aberrant histone modifications include hypoacetylations on tumor suppressor gene regions or hyperacetylations on oncogene regions in endometrial carcinogenesis. These procedures can be biochemically corrected by enzymatic inhibitors. The histone deacetylase inhibitor (HDACi) can inhibit the deacetylation and reactivation of tumor suppressor genes. Similarly, the acetyltransferase inhibitor (HACi) can inhibit the acetylation and inactivation of oncogenes, therefore, these inhibitors are considered to be as the drugs for EC or other cancer treatment.

Histone deacetylation on tumor suppressor in endometrial carcinogenesis

Inactivation of tumor suppressor genes by deacetylation of histone is an important cause of carcinogenesis. A number of tumor suppressor genes have been identified to be associated with endometrial cancer (Table.3). In fact, a lot of evidence for inactivation of tumor suppressor genes by histone deacetylation was derived from those experiments that the deacetylation procedure is inhibited by HDAC inhibitors and resulted in reactivation of tumor suppressor genes [47-49]. Reactivated tumor suppressor gene in EC by HDAC inhibitor was also reported, Sarfstein [50] showed pTEN, P21 (WAF1) were upregulated in type I EC and IGF-IR and P21 were upregulated in type II EC when deacetylation was inhibited by HDAC inhibitor, these results indicated deacetylation of tumor suppressor genes involved in EC carcinogenesis. Interestingly, tumor suppressor gene p53 (in Ishikawa cells) and PTEN (in USPC-2 cells) were down regulated after treatment of these cells with HDAC inhibitor vorinostat, the mechanisms remain unknown, obviously, the HDAC inhibitors act with complicated patterns on the regulation of targets expression. In addition to the histone deacetylation on tumor suppressor in endometrial cancer, deacetylation of tumor suppressor genes are also involved in embryo invasion of endometrial stroma tissue, the TIPM- 1 and TIMP-3 were upregulated after treated endometrial stromal cells with HDAC inhibitor TSA, showed deacetylation of tumor suppressor genes exists not only in endometrial tumor cells but also in normal embryo invasion [51].

Table 3: Histone Modifications in Endometrial Carcinogenesis.




  

    
Target Genes/

      
(Proteins)

      
 

    
Functions of Target Proteins

    
Histone Modifications

      
 

    
Regulation of Expression

    
Tumor Type

    
Reference

  

  

    
APC

      
Bcl-2

      
C/EBPa 

      
Caspase-9

      
CDKs

      
Cyclin A

      
Cyclin D1

      
E-Cadherin

      
Glycodelin

      
IGF-IR

      
MMP-2

      
MMP-9

      
P16

      
P21(WAF1)

      
P27

      
PR-B

      
pRb

      
pTEN,

      
TIG1

      
TIMP-1

      
TIMP-3

    
Tumor    suppressor

      
Oncogene

      
Tumor    suppressor

      
Tumor    Suppressor*

      
Oncogene

      
Oncogene

      
Proto-oncogene

      
Tumor    Suppressor

      
Tumor    suppressor

      
Tumor    Suppressor*

      
Oncogene

      
Oncogene

      
Tumor suppressor

      
Tumor    suppressor

      
Tumor    suppressor

      
Tumor    suppressor

      
Tumor    suppressor**

      
Tumor    suppressor

      
Tumor    suppressor *

      
Tumor    suppressor

      
Tumor    suppressor

    
Methylation

      
?

      
Deacetylation

      
Deacetylation

      
?

      
?

      
?

      
Deacetylation

      
Deacetylation

      
Deacetylation

      
?

      
?

      
Deacetylation

      
Deacetylation

      
Deacetylation

      
Decetylation

      
Deacetylation

      
Deacetylation

      
Deacetylation

      
Deacetylation

      
Deacetylation

    
Downregulation

      
Upregulation

      
Deactivation

      
Deaactivation

      
Upregulation

      
Activation

      
Upregulation

      
Downregulation

      
Deactivation

      
Downregulation

      
Activation

      
Activation

      
Deactivation

      
Deactivation

      
Deactivation

      
Deactivation

      
Upregulation

      
Up/Downregulation

      
Deactivation

      
Deactivation

      
Deactivation

    
EC

      
EC

      
EC

      
EC

      
EC

      
EC, OC

      
EC (type I,    II)

      
EC, OC

      
EC

      
EC (type I,    II)

      
EC

      
EC

      
EC, OC

      
EC

      
EC, OC

      
EC

      
EC

      
EC (type I,    II)

      
EC

      
EC

      
EC

    
(43)

      
(66)

      
(13)

      
(93)

      
(49)

      
(100)

      
(50)

      
(100)

      
(101)

      
(50)

      
(51)

      
(51)

      
(100)

      
(50)

      
(100)

      
(102)

      
(49)

      
(50)

      
(15)

      
(51)

      
(51)

  









Table 3:  Histone Modifications in Endometrial Carcinogenesis.

Histone acetylation on oncogene promoters in endometrial carcinogenesis

Acetylation catalyzes by a class of enzymes called histone acetyltransferases (HATs), HATs belong to a super family, which contains several subgroups as following: 1. Bromodomain-containing group: for instance: P300/CBP, TAFII250, GCN5, ATF2 and etc. [52]; 2. Chromodomain-containing group: Tip60, MOZ Sas3, MORF and etc. [53]; 3. Other family members, some nuclear cofactors such as SRC-1 [54], ACTR [55] and TIF-2 [56], these proteins also display HAT activity therefore is considered as members of HAT family. Similar with deacetylation catalyzed by deacetylase of tumor suppressor genes, theoretically the histone acetylation on oncogenes plays important role in carcinogenesis. A typical example derived from Kang et al. [57], they found HAT inhibitor "curcumin" which biochemically induces histone (H3/H4) hypoacetylation, downregulated the expression of oncogene PARP and Caspase-3, resulted in promotion of apoptosis, differentiation and effective neurogenesis. Unfortunately due to rare EC cases and few researchers are focused on the histone acetylation on oncogenes in EC, the direct evidence of relationship between acetylation on oncogenes and EC carcinogenesis is impossible at present, but some indirect data is still encouraging even there is confuse information, for example. Zhu et al. [58] found acetylation can inhibit the expression of proto-oncogenes such as IGBT3 in endometrial cancer cells (Ishikawa cells) via acetylating HOXA10 at K338 and K339. The acetylation status of core histones on promoter region of oncogenes in EC remains unknown. Undoubtedly, more work is needed to understand the pathological function of deacetylation for oncogenes, which activate through histone acetylation on promoter region in EC carcinogenesis. The acetylation/deacetylation of core histones are dynamic biochemical reactions in cells (Figure 2), the reversible and equilibrated reactions are maintained both by the regulations of network signaling pathways and feedback regulations triggered by microenvironment factors of cell, and also by the regulations of enzymatic kinetics (including substrate concentration and HAT activity). Based on gene expression patterns of cancer cells, any HDACi or HACi may act in a complicated pattern, in other words, one chemical compound modifies core histones at different epigenetic layers, depths and gene promoters depending on both the microenvironment regulation and structure/ conformational-specific interactions, therefore, causes multiple and even opposite results at exteriorly.

The histone acetylation and promoter DNA hypomethylation synergistically activate the oncogene expression in carcinogenesis of endometrial cancer and other cancer types, experiments showed only acetylated histones bind to unmethylated MLH1 promoters, that indicated both of promoter activation by hypomethylation and histone activation by acetylation are required for gene expression [13,59,60].

Epigenetic modification and treatment strategy for endometrial cancer

Treatment of endometrial cancer at epigenetic level by small chemical compounds can partially or even fully restore normal expression level of functional genes including upregulation of inactivated tumor suppressor genes and deactivation of activated oncogenes. At present, inhibition of HDAC activity is one of the most common method for epigenetic treatment of cancers including endometrial cancer, and a number of HDAC inhibitors are developed and being used on clinic trials, some drugs are already into clinic phase III such as TSA (Trichostatin A) [61], which inhibits almost all of the HDAC members but HDAC8, the biological function of this epigenetic drug includes: 1, induce apoptosis of cancer cells; 2, induce cancer cell differentiation. Panobinostat is a novel HDAC inhibitor with a broad-spectrum HDAC inhibition activity developed by Novartis Company and has been used to against many type of cancers [62], this drug has been shown to inhibit proliferation and induce apoptosis of EC cells. Tacedinaline (CI994) is also a HDAC inhibitor newly developed by Pfizer Company that has been used in phase III clinical trial [63], and the biological function for this drug included mediation of G1 cell cycle arrest, inhibition of proliferation and induction of apoptosis of cancer cells. At present more than 30 compounds are being used for preclinical or early stage clinical trials for the inhibition of HDAC activity such as Dacinostat, Sodium phenylbutyrate, CUDC-907, Tubastatin, Tubacin, Givinostat.

Since silence of tumor suppressor genes by promoter hypermethylation also plays an important role in the development and progression of EC, therefore another valuable target for epigenetic therapy of endometrial cancer is to directly inhibit DNA methyltransferase activity. At present, the most popular DNMT inhibitors (DNMTi) both for experimental and clinical purpose are cytidine analogues such as 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine) and pyrimidin-2-one ribonucleoside (zebularine). Experiment showed that DNMTi (decitabine) induces apoptosis, growth inhibition and G2 arrest in human endometrial cancer cells [64]. The combination of DNMTi and HDACi as a new treatment strategy showed better efficacy to cancer patients compared with separated administration. Xu et al [65] recently reported the presence of strong synergistic effect between DMNTi (ADC) and HDACi (TSA), TSA appeared to be a more potent apoptosis inducer, but have smaller effect on cell cycle, in the reverse effect; ADC exhibited strong regulation on cell cycle, but had smaller effect on apoptosis. Yi et al. [66] showed combination of DNMTi (ADC) and HDACi (VPA, valproic acid) treatment inhibited tumor growth of endometrial cell lines (HEC1B), and upregulated CDH1 and downregulated Bcl-2 expression levels. Doubtlessly, treatment of endometrial cancer with administration of both inhibitors for DNMTs and for HDACs should be one of the major methods for epigenetic therapy of endometrial cancer in the future.

Summary

It becomes clear that the initiation, progression and metastasis of endometrial cancer are controlled both by genetic and epigenetic events. Genetic alterations associated with EC carcinogenesis involve several critical genetic events such as high frequent mutations of PTEN, K-RAS, P53 etc., and these genetic changes result in interfering corresponding signaling pathways (for examples: PI3K/AKT/mTOR; WNT/β-catenin, MAPK/ERK and etc.), and thereafter the cells obtain the transforming capabilities to form the endometrial cancer phenotype. At the layer of modifications for DNA and core histones, epigenetic alterations also play an important role in EC carcinogenesis (Figure 3), for most EC cases, the genetic and epigenetic alterations are both existed and may have synergistic effect, for example: PTEN acts as a key mediator of signaling pathway involved in endometrial cancer due to frequent mutations, interestingly, this gene has also been detected with histone deacetylation on promoter region for these endometrial cancer cases. Other genes such as P16 or pRB were also frequently detected with genetic alterations or epigenetic alterations. These alterations at genetic and epigenetic levels show a potential, encouraging possibility for endometrial cancer treatment, which means by targeting both levels, the malignant phenotype can be reverted to normal state through adjusting the expression of target genes at epigenetic layer.

Figure 3:

The Epigenetic Modifications and Endometrial Carcinogenesis.

The chromatin consists of the nucleosome, which comprises a sequence of DNA wrapped around core histones. The cis elements existed in DNA sequences such as promoters are abnormally modified including promoter hypermethylation of tumor suppressor genes, promoter hypomethylation of oncogenes. On the other hand, the aberrant core histone modifications such as deacetylation or site- specific methylations of histones on tumor suppressor genes, demethylation or acetylations of histone on oncogenes are co-operationally interactions with DNA alterations to interfere the gene expression and promote the carcinogenesis of endometrial cancer.






Figure 3:  
The Epigenetic Modifications and Endometrial Carcinogenesis.


The chromatin consists of the nucleosome, which comprises a sequence of DNA wrapped around core histones. The cis elements existed in DNA sequences such as promoters are abnormally modified including promoter hypermethylation of tumor suppressor genes, promoter hypomethylation of oncogenes. On the other hand, the aberrant core histone modifications such as deacetylation or site- specific methylations of histones on tumor suppressor genes, demethylation or acetylations of histone on oncogenes are co-operationally interactions with DNA alterations to interfere the gene expression and promote the carcinogenesis of endometrial cancer.

The methylation/demethylation of DNA and acetylation/ deacetylation of histones are the most common and important epigenetic modifications in normal and cancer cells. Critical issues for exploring epigenetic alterations will need to understand the following aspects: 1, understand how global hypomethylations and local hypermethylations (located in promoter region of tumor suppressor genes) take place in carcinogenesis; 2, how to regulate the reversible reactions for these epigenetic modifications in normal and cancer cells; 3, the most challenging work is site- or position-specific modifications for the DNAs or histones in chromatin, since epigenetic drugs (HDACi, DMNTi) may randomly reactivate tumor suppressor genes and also activate proto-oncogenes at same time; 4, explore the relationships between daily nutrients containing methyl or acetyl groups which are critical substrates for epigenetic modifications and may involve in carcinogenesis or anti-carcinogenesis.

Acknowledgment

We are very grateful to Dr. Jeffrey Sklar for reading the manuscript and his critical comments.

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Citation: Ma X, Gao X. Epigenetic Modifications and Carcinogenesis of Human Endometrial Cancer. Austin J Clin Pathol. 2014;1(3): 1014. ISSN : 2381-9170