Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma

Gong, Fuyu; Guo, Yu; Niu, Yiqian; Jin, Jiawei; Zhang, Xiaojuan; Shi, Xiaoqian; Zhang, Limeng; Zhao, Yuanli; Chen, Longxin; Runlin, Z.

doi:10.18632/oncotarget.13324

Cited by 37 publications

(28 citation statements)

References 37 publications

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“…027008-14 128(2) February 2020 possible involvement of the promoter methylation of the TET2 gene. The methylation of CpG islands in the promoter region of genes is a well-known inhibitory mechanism for down-regulation of gene and protein expression (Figueroa et al 2010;Gong et al 2017). The hypermethylation of TET1 gene has been found in multiple primary tumors (Li et al 2016), and DNMT3A-mediated methylation of TET2 and TET3 promoters has been implicated in the induction of the epithelial-mesenchymal transition-like process and metastasis in melanoma (Gong et al 2017).…”

Section: Environmental Health Perspectivesmentioning

confidence: 99%

“…The methylation of CpG islands in the promoter region of genes is a well-known inhibitory mechanism for down-regulation of gene and protein expression (Figueroa et al 2010;Gong et al 2017). The hypermethylation of TET1 gene has been found in multiple primary tumors (Li et al 2016), and DNMT3A-mediated methylation of TET2 and TET3 promoters has been implicated in the induction of the epithelial-mesenchymal transition-like process and metastasis in melanoma (Gong et al 2017). TET2 promoter methylation has been implicated in lymphoblastic leukemia (Figueroa et al 2010;Musialik et al 2014) and has also been reported in a small fraction (4.4%) of myeloproliferative neoplasms (Chim et al 2010).…”

Section: Environmental Health Perspectivesmentioning

confidence: 99%

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Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Lyu

Ren

et al. 2020

Environ Health Perspect

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BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor targeting estrogen receptors (ERs), has been implicated in the promotion of breast cancer. Perinatal exposure of BPA could induce longitudinal alteration of DNA hydroxymethylation in imprinted loci of mouse blood cells. To date, no data has been reported on the effects of BPA on DNA hydroxymethylation in breast cells. Therefore, we asked whether BPA can induce DNA hydroxymethylation change in human breast cells. Given that dysregulated epigenetic DNA hydroxymethylation is observed in various cancers, we wondered how DNA hydroxymethylation modulates cancer development, and specifically, whether and how BPA and its analogs promote breast cancer development via DNA hydroxymethylation. OBJECTIVES: We aimed to explore the interplay of the estrogenic activity of bisphenols at environmental exposure dose levels with TET dioxygenase-catalyzed DNA hydroxymethylation and to elucidate their roles in the proliferation of ER + breast cancer cells as stimulated by environmentally relevant bisphenols. METHODS: Human MCF-7 and T47D cell lines were used as ER-dependent breast cell proliferation models, and the human MDA-MB-231 cell line was used as an ER-independent breast cell model. These cells were treated with BPA or bisphenol S (BPS) to examine BPA/BPS-related proliferation. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and enzyme-linked immunosorbent assays (ELISAs) were used to detect DNA hydroxymethylation. Crispr/Cas9 and RNA interference technologies, quantitative polymerase chain reaction (qPCR), and Western blot analyses were used to evaluate the expression and function of genes. Co-immunoprecipitation (Co-IP), bisulfite sequencing-PCR (BSP), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to identify the interactions of target proteins. RESULTS: We measured higher proliferation in ER + breast cancer cells treated with BPA or its replacement, BPS, accompanied by an ERa-dependent decrease in genomic DNA hydroxymethylation. The results of our overexpression, knockout, knockdown, and inhibition experiments suggested that TET2-catalyzed DNA hydroxymethylation played a suppressive role in BPA/BPS-stimulated cell proliferation. On the other hand, we observed that TET2 was negatively regulated by the activation of ERa (dimerized and phosphorylated), which was also induced by BPA/BPS binding. Instead of a direct interaction between TET2 and ERa, data of our Co-IP, BSP, and ChIP-qPCR experiments indicated that the activated ERa increased the DNA methyltransferase (DNMT)-mediated promoter methylation of TET2, leading to an inhibition of the TET2 expression and DNA hydroxymethylation. CONCLUSIONS: We identified a new feedback circuit of ERa activation-DNMT-TET2-DNA hydroxymethylation in ER + breast cancer cells and uncovered a pivotal role of TET2-mediated DNA hydroxymethylation in modulating BPA/BPS-stimulated proliferation. Moreover, to our knowledge, we for the first time established a linkage among...

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Section: Environmental Health Perspectivesmentioning

confidence: 99%

Section: Environmental Health Perspectivesmentioning

confidence: 99%

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Lyu

Ren

et al. 2020

Environ Health Perspect

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“…However, the sole use of DNMT inhibitors in melanoma treatment has yielded mixed results, which might be due to the heterogenicity of tumors and the overall epigenetic alterations. Moreover, reduced expression of TET2 in melanoma may provide novel options [ 88 – 89 ]. As discussed above, the DNA methylation status has been observed to be low in the neoplastic progression of carcinogenesis.…”

Section: Dna Methylation and Hydroxymethylationmentioning

confidence: 99%

DNA methylation/hydroxymethylation in melanoma

Zhang

et al. 2017

Oncotarget

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Melanoma is a malignant tumor of melanocytes and is considered to be the most aggressive cancer among all skin diseases. The pathogenesis of melanoma has not been well documented, which may restrict the research and development of biomarkers and therapies. To date, several genetic and epigenetic factors have been identified as contributing to the development and progression of melanoma. Besides the findings on genetic susceptibilities, the recent progress in epigenetic studies has revealed that loss of the DNA hydroxymethylation mark, 5-hydroxymethylcytosine (5-hmC), along with high levels of DNA methylation at promoter regions of several tumor suppressor genes in melanoma, may serve as biomarkers for melanoma. Moreover, 5-Aza-2′-deoxycytidine, an epigenetic modifier causing DNA demethylation, and ten-eleven translocation family dioxygenase (TET), which catalyzes the generation of 5-hmC, demonstrate therapeutic potential in melanoma treatment. In this review, we will summarize the latest progress in research on DNA methylation/hydroxymethylation in melanoma, and we will discuss and provide insight for epigenetic biomarkers and therapies for melanoma. Particularly, we will discuss the role of DNA hydroxymethylation in melanoma infiltrating immune cells, which may also serve as a potential target for melanoma treatment.

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“…Epithelial-mesenchymal transition (EMT) is a critical event for the initiation of tumor malignancy. During tumor progression, EMT can induce increased migration and invasion (Alonso et al, 2007;Voon et al, 2012;Gong et al, 2017), and the EMT-like process also plays a key role in melanoma malignancy (Alonso et al, 2007;Gong et al, 2017). Runx3 reportedly induces the epithelioid transformation of fibroblasts (Wotton et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Runx3 inhibits melanoma cell migration through regulation of cell shape change

Zhang

Wang

Zeng

et al. 2017

Cell Biology International

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The transcription factor Runx3 is a known tumor suppressor gene, and its expression is frequently lost in melanoma. However, the potential contribution of the loss of Runx3 expression to melanoma development and progression remains unclear. In this in vitro study, we demonstrated that ectopic Runx3 re-expression in B16-F10 melanoma cells changed the cell shape from elongated and branched to spread and unbranched, which enhanced stress fiber formation, increased the number of mature and fibrillar focal adhesions, and up-regulated fibronectin expression. In association with the cell shape change, the Runx3 re-expression in B16-F10 melanoma cells inhibited cell migration. Moreover, the phenotype of the Runx3 induced cell shape change was partially resembled when the melanoma cells were cultured on a fibronectin-coated coverslip, suggesting that fibronectin may mediate the Runx3 induced cell shape change of the melanoma cells. Taken together, our findings suggest that Runx3 may regulate cell shape to inhibit melanoma cell migration partly through enhancing stress fiber formation and ECM protein production. Our present study provides further evidence for the idea that cell shape change is potentially correlated with melanoma development and progression.

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Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma

Cited by 37 publications

References 37 publications

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

DNA methylation/hydroxymethylation in melanoma

Runx3 inhibits melanoma cell migration through regulation of cell shape change

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