DNMT3A and DNMT3B in Breast Tumorigenesis and Potential Therapy

Man, Xiaxia; Li, Qi; Wang, Baogang; Zhang, He; Zhang, Songling; Li, Ziyi

doi:10.3389/fcell.2022.916725

Cited by 32 publications

(19 citation statements)

References 88 publications

(93 reference statements)

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“…12 DNA methyltransferase 3A (DNMT3A) is a de novo methyltransferase necessary for mammalian development. 13 As previously illustrated, DNMT3A expression was markedly increased in the ectopic endometrium tissues of women with EMs. 14 In addition, the role of DNMT3A in regulating fibrosis has been widely studied.…”

Section: Introductionmentioning

confidence: 62%

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Endometriotic mesenchymal stem cells promote the fibrosis process of endometriosis through paracrine TGF‐β1 mediated RASAL1 inhibition

Feng,

Dong,

Tan

2023

J of Obstet and Gynaecol

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BackgroundEndometrial‐derived stem cells are key players in endometriosis (EMs) pathogenesis, while the mechanism involved is still unclear. Herein, the role and regulatory mechanism of endometriotic mesenchymal stem cells (ecto‐MSCs) in regulating fibrosis during EMs progression were investigated.MethodsThe mRNA and protein expressions were assessed using qRT‐PCR, western blot, and immunofluorescence. Flow cytometry was adopted to analyze the markers of MSCs. Transwell assay was adopted to examine endometriotic stromal cells (ESCs) migration and invasion. The interactions between DNMT3A and RASAL1 were analyzed by ChIP assay. In addition, MSP was employed to detect RASAL1 promoter methylation level.ResultsEcto‐MSCs promoted ESCs migration, invasion, and fibrosis process by TGF‐β1 paracrine. It was subsequently revealed that TGF‐β1 upregulated DNMT3A in ESCs in a SMAD3‐dependent manner. As expected, DNMT3A knockdown abolished ecto‐MSCs' facilitation on ESCs migration, invasion, and fibrosis process. DNMT3A, as a methyltransferase, reduced RASAL1 expression in TGF‐β1‐treated ESCs by increasing RASAL1 promoter methylation level. RASAL1, as an antifibrotic protein, was lowly expressed in TGF‐β1‐treated ESCs, and its overexpression ameliorated TGF‐β1‐induced increase in ESCs migration, invasion, and fibrosis process.ConclusionTGF‐β1 secreted by ecto‐MSCs facilitated fibrogenesis in EMs through SMAD3/DNMT3A‐mediated RASAL1 inhibition.

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Section: Introductionmentioning

confidence: 62%

“…DNA methylate modification is regulated by methyltransferase and demethylase 12 . DNA methyltransferase 3A (DNMT3A) is a de novo methyltransferase necessary for mammalian development 13 . As previously illustrated, DNMT3A expression was markedly increased in the ectopic endometrium tissues of women with EMs 14 .…”

Section: Introductionmentioning

confidence: 75%

Endometriotic mesenchymal stem cells promote the fibrosis process of endometriosis through paracrine TGF‐β1 mediated RASAL1 inhibition

Feng,

Dong,

Tan

2023

J of Obstet and Gynaecol

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“…DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines. DNMT3A overexpression has been widely reported in breast cancer (Man et al, 2022). Together with the basic helixloop-helix transcription factor (MYC), DNMT3A represses the transcription of miR-200b in triple-negative breast cancer cells (Pang et al, 2018).…”

Section: Tablementioning

confidence: 99%

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Tuo¹,

LIU²

2023

Biocell

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Retinoic acid receptor responder 3 (RARRES3) has been characterized as a tumor suppressor in multiple types of cancer. This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer. The DNA methylation status of RARRES3 was checked in the basal-like subtype, and the underlying mechanisms of its dysregulation were explored. RNA-sequencing (seq) and methylation data from The Cancer Genome Atlas were used for in-silico analysis. Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues, only the basal-like tumor tissues had significantly downregulated RARRES3 expression. The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression. The gene coding for DNA methyltransferase 3A (DNMT3A) had consistent positive correlations with the methylation of the CpG sites. Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region. DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines. CCK-8, colony formation, and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling. In summary, this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer. The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.

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“…DNMT1 is primarily responsible for maintaining methylation, while DNMT3a and DNMT3b are involved in de novo methylation. 22 DNMT3a/DNMT3b can actively introduce methylation into DNA to regulate gene expression, which plays a pivotal role in carcinogenesis. 23 Clinical data and gain-and loss-of-function studies have yielded evidence suggesting that EZH2 plays an oncogenic role in CCA.…”

Section: Introductionmentioning

confidence: 99%

“…Generally, DNMTs regulate DNA methylation, with three common isoforms identified in humans: DNMT1, DNMT3a and DNMT3b. DNMT1 is primarily responsible for maintaining methylation, while DNMT3a and DNMT3b are involved in de novo methylation 22 . DNMT3a/DNMT3b can actively introduce methylation into DNA to regulate gene expression, which plays a pivotal role in carcinogenesis 23 …”

Section: Introductionmentioning

confidence: 99%

Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

Wu,

Wang,

Wang

et al. 2023

Clinical & Translational Med

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BackgroundCholangiocarcinoma (CCA) refers to a collection of malignancies that are associated with a dismal prognosis. Currently, surgical resection is the only way to cure patients with CCA. Available systemic therapy is limited to gemcitabine plus cisplatin; however, this treatment is palliative in nature. Therefore, there is still a need to explore new effective therapeutic targets to intervene against CCA.MethodsWe analyzed the expression of EZH2 and the prognosis of patients in CCA. The proliferation, migration and invasion of CCA cells after gene knockdown and overexpression were examined and validated by a xenograft model and a primary CCA mouse model with corresponding gene intervention. Targeting DNA methylation, and RNA‐sequencing‐based transcriptomic analysis in EZH2 and SUZ12 knockout CCA cells was performed. Bisulfite sequencing polymerase chain reaction (PCR), chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) and reverse‐ChIP assays were performed for research purposes.ResultsIncreased expression of EZH2 in CCA exhibited a significantly poorer prognosis. DNA hypomethylation of the promoter and increased mRNA levels of secreted frizzled‐related protein 1 (SFRP1) were observed in CCA cells following the inhibition of polycomb repressor complex 2 (PRC2), which was achieved through a knockout of EZH2, SUZ12 and EED, respectively, or treatment with GSK126 and GSK343. Targeting the SFRP1 promoter DNA hypermethylation with dCas9‐DNMT3a decreased the mRNA level of SFRP1. The expression of SFRP1 is regulated by both H3K27me3 and DNA methylation and H3K27me3 plays a crucial role in promoting SFRP1 promotor DNA methylation. GSK343 is a small molecule inhibitor that targets the catalytic activity of EZH2. It effectively inhibits the progression and development of subcutaneous xenografts and primary CCA mouse models.ConclusionOverall, our data strongly suggested that targeting PRC2 promotes the expression of SFRP1, thereby inhibiting the progression of CCA.Key Points/Headlights Cholangiocarcinoma (CCA) exhibits elevated expression of EZH2, SUZ12 and EED, resulting in increased levels of H3K27me3. Targeting polycomb repressor complex 2 (PRC2) leads to the removal of H3K27me3 from the secreted frizzled‐related protein 1 (SFRP1) promoter and DNA hypomethylation, thereby activating the transcription of SFRP1. Inhibiting PRC2, including the use of EZH2 inhibitors, holds promise as a potential strategy for developing anti‐cancer drugs for CCA.

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DNMT3A and DNMT3B in Breast Tumorigenesis and Potential Therapy

Cited by 32 publications

References 88 publications

Endometriotic mesenchymal stem cells promote the fibrosis process of endometriosis through paracrine TGF‐β1 mediated RASAL1 inhibition

Endometriotic mesenchymal stem cells promote the fibrosis process of endometriosis through paracrine TGF‐β1 mediated RASAL1 inhibition

Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer

Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

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