*3.2.1. TET1 methylation-mediated activation of tumor suppressor genes*

It is acknowledged that 5hmC depletion initiates carcinogenesis caused by either TET1 expression repression or aberrant localization. Significantly lower 5-hmC and TET1 expression level and subcellular mislocalization in gastric cancer tissues demonstrate the crucial role of TET1 as a cancer repressor [97] (**Figure 3**).

In the tested epithelial ovarian cancer (EOC), undetected TET1 expression suggests that the consequence of TET1 repression induces the tumorigenesis, in accordance with the inhibition

**Figure 3.** TET1 functions as a tumor suppressor. (A) In normal cells, TET1 expression is maintained at a regular level. The TET1 is recruited to the methylated promoter area of the tumor suppressor genes for demethylation so that the tumor suppressor could be expressed at the normal levels. (B) Due to mutation of the Tet1 genes or some other factors, Tet1 expression silenced, leading to silencing of the suppressor genes and activation of the oncogenes such as Ezh2. Expression of the oncoproteins initiates the tumorigenesis or enhances cancer cell growth and metastasis.

of colony formation, cell migration, and invasion by ectopic expression of TET1 in SKOV3 and OVCAR3 cells. The potential mechanism is the TET1 conferred demethylation and the consequent activation of the expression of two key proteins SFRP2 and DKK1 in the canonical Wnt/βcatenin signaling pathway, associated with inhibition of EMT and metastasis [101].

TET1 is identified as a key tumor suppressor player in ovarian cancer cell lines as well by demethylating a CpG site within the Ras association domain family member 5 (RASSF5) promoter to enhance expression of the RASSF5, leading to the growth inhibition of ovarian cancer cells [102].

More evidences show that EGFR-mediated TET1 repression induces silencing of tumor suppressors in cancer cells such as lung adenocarcinomas and glioblastomas. If only the oncogenic EGFR expression is inhibited, TET1 could bind to promoters of the tumor suppressors to activate their expression via DNA demethylation. TET1 overexpression inhibits lung and glioblastoma tumor growth, and vice versa, in agreement with the significant decrease in TET1 expression or TET1 cytoplasmic localization in the majority of lung cancer samples. Thus, it is plausible to speculate that TET1 may serve as the therapeutic target for oncogenic EGFR-induced lung cancers and glioblastomas [93]. However, Lai et al. could not draw the same conclusion in human NSCLC patient samples. They did not detect the EGFR-mediated TET1 silencing, but rather observed the significant elevation of the TET1 expression levels in patient samples with EGFR mutations, suggesting the inconclusiveness in EGFR-mediated TET1 silencing among the cellular and animal models and human lung cancer patients [94].

Eicosapentaenoic acid (EPA), one of the major polyunsaturated fatty acids, could enhance the formation of PPARγ-RXRα-TET1 to recruit TET1 to a hypermethylated CpG island on the p21 gene for rapid demethylation and consequent expression of p21Waf1/Cip1, leading to inhibition of cancer cell-cycle progression in hepatocarcinoma cells. This suggests the bridge requirement for TET1 exerting the anti-tumor function and potential of EPA for solid tumor therapy such as live cancer [97].

### *3.2.2. TET1 silencing and loss of 5-hmC induces initiation of tumors*

Loss of 5-hydroxymethylcytosine (5 hmC) caused by TET1 dysfunction could induce tumor initiation and enhance malignancy by promoting cancer cell growth, migration, and invasion in DLD1 colon cancer cells mediated by EZH2 [96]. With loss of TET1, EZH2 repression is released, but H3K27 demethylase UTX-1 expression is repressed, enhancing histone H3K27 tri-methylation and consequently repressing the target gene E-cadherin (DH1). Accordingly, even at the condition of TET1 deficiency, either the H3K27 demethylase UTX-1 overexpression or EZH2 depletion both could enhance H3K27 demethylation at CDH1 promoter, thereby impeding EMT and tumor invasion. Likewise, either EZH2 overexpression or UTX-1 depletion both could promote EMT and tumor metastasis in DLD1 cells. Thus, these results elucidate regulation interplay among TET1, E-cadherin, and EZH2 and indicate the critical mediator role the EZH2 plays in the E-cadherin repression and tumor progression [95].

#### *3.2.3. miRNA-mediated repression of TET1 expression*

**Figure 3.** TET1 functions as a tumor suppressor. (A) In normal cells, TET1 expression is maintained at a regular level. The TET1 is recruited to the methylated promoter area of the tumor suppressor genes for demethylation so that the tumor suppressor could be expressed at the normal levels. (B) Due to mutation of the Tet1 genes or some other factors, Tet1 expression silenced, leading to silencing of the suppressor genes and activation of the oncogenes such as Ezh2.

mRNA sequestrates miR-26 competitively and leads to release of the miR-26 mediated repression of EZH2. Thus, activation of EZH2 expression facilitates gastric carcinogenesis and pro-

The pathogenic contributions the TET members made in various human cancers by functioning as tumor suppressors or promoters have been proven to be versatile. The hypermethylationbased transcriptional silencing of TET1 is frequently detected in non-Hodgkin B cell lymphoma (B-NHL), suggesting TET1 as a tumor suppressor of hematopoietic malignancy [91]. Similarly, TET1 is downregulated upon NF-κB activation in multiple cancers including basal-like breast cancer (BLBC), melanoma, lung, and thyroid cancers, demonstrating that TET1 is the tumor

It is acknowledged that 5hmC depletion initiates carcinogenesis caused by either TET1 expression repression or aberrant localization. Significantly lower 5-hmC and TET1 expression level and subcellular mislocalization in gastric cancer tissues demonstrate the crucial role of TET1

In the tested epithelial ovarian cancer (EOC), undetected TET1 expression suggests that the consequence of TET1 repression induces the tumorigenesis, in accordance with the inhibition

gression [87] (**Figure 2**).

194 Chromatin and Epigenetics

**3.2. TET1 serves as a tumor suppressor**

as a cancer repressor [97] (**Figure 3**).

suppressor that relies on involvement of the immune system [92].

*3.2.1. TET1 methylation-mediated activation of tumor suppressor genes*

Expression of the oncoproteins initiates the tumorigenesis or enhances cancer cell growth and metastasis.

Some miRNAs are identified to be involved in regulation of cancer progression or repression, and one of the mechanisms refers to the oncogenic miRNA-mediated TET1 repression and the consequent loss of 5-hmC. Indeed, miR-21-5p has been confirmed to target Tet1 in colorectal cancer (CRC), serving as a biomarker for diagnostics and prognostics in CRC [98]. Similarly, miR-4284 directly targeting Tet1 mRNA downregulates TET1 levels of both mRNA and protein in human gastric cancer SGC-7901 cells, and thus serves as an oncogenic marker [99], suggesting that miR-4284 could provide a potential target for gastric cancer therapy.

landscape, it is essential to investigate how the epigenetic information stored in the landscape is transformed into the biological effect. To this end, for identification of the readers of the 5-hmC modification, the specific 5-hmC binding proteins might be the prerequisite. A better understanding the functions of methyltransferase complex for cytosine methylation, TETs for demethylation of 5-mC and interaction protein components as well as the other known functions, and the specific readers of the 5-hmC marker could identify some epigenetic components for therapeutic targets for treatments of cancers and other diseases such as

Cytosine Modifications and Distinct Functions of TET1 on Tumorigenesis

http://dx.doi.org/10.5772/intechopen.83709

197

It has been reported that Tet1 alternative splicing forms have distinct functions [74]. However, the information regarding the Tet1 alternative splicing is still limited. Further alternative splicing study may identify more unknown functions conferred by the different isoforms which

Additionally, the chemical biology approach based on further identification of small molecule compounds that target the 5-mC/5-hmC machineries or the signaling pathways in which 5-mC/5-hmC involved could help explore therapeutic targets for some stubborn diseases such

\*

1 Department of Internal Medicine, Qingdao Agricultural University Associated Hospital,

2 Department of Nutrition and Food Science, Texas A&M University, College Station, TX,

4 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

[1] Dupont C, Armant DR, Brenner CA.Epigenetics: Definition, mechanisms and clinical perspective. Seminars in Reproductive Medicine. 2009;**27**(5):351-357. DOI: 10.1055/s-0029-

[2] Soubry A. Epigenetics as a driver of developmental origins of health and disease: Did we forget the Fathers? BioEssays. 2018;**40**(1):1700113. DOI: 10.1002/bies.201700113

[3] Joshita S, Umemura T, Tanaka E, Ota M. Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clinical Journal of Gastroenterology. 2018;**11**(1):11-18. DOI:

3 Department of Neurology of Xiangya Hospital, Central South University, Changsha,

neurological disorders.

**Author details**

Cuili Ma1

USA

Hunan, China

**References**

1237423

10.1007/s12328-017-0799-z

may bear the potential for therapeutic targets.

, Nina Xie3

\*Address all correspondence to: yli29@emory.edu

and Yujing Li4

as cancers and neurological diseases.

, Pengfei Ji2

Qingdao, Shandong, PR China
