Clinicopathological Significance and Prognostic Value of DNA Methyltransferase 1, 3a, and 3b Expressions in Sporadic Epithelial Ovarian Cancer

Bai, Xuefeng; Song, Zhiguo J.; Fu, Yingzi; Yu, Zhaojin; Zhao, Lin; Zhao, Hang; Yao, Weifan; Huang, Desheng; Mi, Xiaoyi; Wang, Enhua; Zheng, Zhaohui

doi:10.1371/journal.pone.0040024

Cited by 39 publications

(38 citation statements)

References 52 publications

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“…The association of DNMT1 expression with lymph node metastasis is also found in pancreatic cancer . but not in ovary cancer and gastric cancer. The role of DNMT1 in lymph node metastasis appears to be associated with different mechanisms in different cancers.…”

Section: Discussionmentioning

confidence: 93%

DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis

Xiao

Zhao

et al. 2014

Mol. Carcinog.

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DNA methyltransferases (DNMTs), including DNMT1, 3a, and 3b, play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of DNMTs is associated with the development of breast cancer. This study aimed to explore the clinical significance of DNMT proteins in sporadic breast cancer. We investigated the expression of DNMT1, 3a, and 3b in 256 breast cancer and 36 breast fibroadenoma, using immunohistochemistry. The expression of DNMT1 and 3a was significantly higher in breast cancer than in fibroadenoma. In breast cancer, the expression of DNMT1 was significantly correlated with lymph node metastasis (P = 0.020), and the expression of DNMT3a and 3b was significantly correlated with advanced clinical stages (P = 0.046 and 0.012, respectively). Overexpression of DNMT1/3a was correlated with promoter hypermethylation and reduced expression of ERα and BRCA1. The expression levels of DNMT1 or DNMT3a were associated with a significantly shorter DFS or OS in a subgroup of breast cancer patients (patients with the age ≤50 years old, ERα-negative status, or HER2-postive status). The expression of DNMT1 or a combined expression of DNMT1 and 3a was associated with poor prognosis in patients who received chemotherapy and endocrine therapy, but not in patients who received chemotherapy alone. These findings suggest that DNMT1 and 3a may be involved in the progression and prognosis of sporadic breast cancer.

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Section: Discussionmentioning

confidence: 93%

DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis

Xiao

Zhao

et al. 2014

Mol. Carcinog.

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“…Deregulated levels of DNMTs have been reported in cancer (31) and in OC (32,33), and in association with platinum resistance. Therefore, DNMT1, 3A and 3B expression levels were measured in platinum sensitive (A2780) and resistant (A2780_CR5) sublines and in A2780_CR5 derived ALDH(+) and ALDH(−) cells.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Targeting of Ovarian Cancer Stem Cells

et al. 2014

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Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer (OC). As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cell (OCSC). In this study, we tested the hypothesis that DNA hypomethylating agents may be able to reset OCSC towards a differentiated phenotype, by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH+ OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stem-like properties of ALDH+ cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by re-programming residual cancer stem-like cells. Further, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.

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“…DNMT3A and DNMT3B are responsible for de novo methylation in the genome, whereas DNMT1 is responsible for maintaining methylation in the genome. DNMT3A and DNMT3B have been reported to be upregulated in ovarian cancers . They are both able to hypermethylate the promoter region in microRNA (miR) precursor genes and thus inversely regulate miR transcription …”

Section: Introductionmentioning

confidence: 99%

Double‐negative feedback interaction between DNA methyltransferase 3A and microRNA‐145 in the Warburg effect of ovarian cancer cells

Zhang

Pei

et al. 2018

Cancer Science

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Ovarian cancer is the most lethal gynecological malignancy because of its poor prognosis. The Warburg effect is one of the key mechanisms mediating cancer progression. Molecules targeting the Warburg effect are therefore of significant therapeutic value for the treatment of cancers. Many microRNAs (miR) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with the Warburg effect in cancer cells. In our study, we found that miR‐145 negatively correlated with DNA methyltransferase (DNMT)3A expression at cellular/histological levels. miR‐145 inhibited the Warburg effect by targeting HK2. Luciferase reporter assays confirmed that miR‐145‐mediated downregulation of DNMT3A occurred through direct targeting of its mRNA 3′‐UTRs, whereas methylation‐specific PCR (MSP) assays found that knockdown of DNMT3A increased mRNA level of miR‐145 and decreased methylation levels of promoter regions in the miR‐145 precursor gene, thus suggesting a crucial crosstalk between miR‐145 and DNMT3A by a double‐negative feedback loop. DNMT3A promoted the Warburg effect through miR‐145. Coimmunoprecipitation assays confirmed no direct binding between DNMT3A and HK2. In conclusion, a feedback loop between miR‐145 and DNMT3A is a potent signature for the Warburg effect in ovarian cancer, promising a potential target for improved anticancer treatment.

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Clinicopathological Significance and Prognostic Value of DNA Methyltransferase 1, 3a, and 3b Expressions in Sporadic Epithelial Ovarian Cancer

Cited by 39 publications

References 52 publications

DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis

DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis

Epigenetic Targeting of Ovarian Cancer Stem Cells

Double‐negative feedback interaction between DNA methyltransferase 3A and microRNA‐145 in the Warburg effect of ovarian cancer cells

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