Multi-target siRNA based on DNMT3A/B homologous conserved region influences cell cycle and apoptosis of human prostate cancer cell line TSU-PR1

Du, Yifan; Liang, Liang; Shi, Ying; Long, Qi; Zeng, Jin; Wang, Xin-Yang; He, Dalin

doi:10.1590/s1415-47572012005000021

Cited by 8 publications

(5 citation statements)

References 24 publications

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“…DNA methyltransferase dysregulation has frequently been reported in malignant tumors, including leukemia, prostate cancer, and gastric cancer . We observed that treatment of SKOV3 and 3AO cells with 5‐Aza‐CdR resulted in increased miR‐145 levels, suggesting that miR‐145 expression in EOC cells might be regulated by DNA methylation.…”

Section: Discussionmentioning

confidence: 79%

“…DNA methyltransferase dysregulation has frequently been reported in malignant tumors, including leukemia, prostate cancer, and gastric cancer. [24][25][26] We observed that treatment of SKOV3 Increasing evidence has shown that these DNMT work together to maintain a normal methylation pattern, and deregulation of either one could promote malignancies. 27 More recently, DNMT3A has been reported to participate in epithelial-mesenchymal transition (EMT).…”

Section: Expression Of Hk2 and Dnmt3a In Ovarian Cancer Tissue Subcmentioning

confidence: 90%

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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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Section: Discussionmentioning

confidence: 79%

Section: Expression Of Hk2 and Dnmt3a In Ovarian Cancer Tissue Subcmentioning

confidence: 90%

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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“…Among the three DNMTs, DNMT3B has been consistently shown to increase its levels in transformed vs. normal prostate tissue, both in patient tumors and in cell lines [ 34 – 37 ] and its expression increase along with adverse clinical parameters [ 36 , 37 ]. Functional studies in siRNA cell lines, cadmium-transformed prostate epithelial cells and TRAMP mouse models [ 35 , 38 , 39 ], together with the association between PrCa risk and a polymorphism in DNMT3B leading to increased enzyme expression [ 40 ], have provided further support to this hypothesis. Thus, DNMT3B seems to be the most important DNMT driver in PrCa.…”

Section: Discussionmentioning

confidence: 99%

Nc886 is epigenetically repressed in prostate cancer and acts as a tumor suppressor through the inhibition of cell growth

et al. 2018

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BackgroundNc886 is a 102 bp non-coding RNA transcript initially classified as a microRNA precursor (Pre-miR-886), later as a divergent homologue of the vault RNAs (vtRNA 2–1) and more recently as a novel type of RNA (nc886). Although nc886/vtRNA2–1/Pre-miR-886 identity is still controversial, it was shown to be epigenetically controlled, presenting both tumor suppressor and oncogenic function in different cancers. Here, we study for the first time the role of nc886 in prostate cancer.MethodsNc886 promoter methylation status and its correlation with patient clinical parameters or DNMTs levels were evaluated in TCGA and specific GEO prostate tissue datasets. Nc886 level was measured by RT-qPCR to compare normal/neoplastic prostate cells from radical prostatectomies and cell lines, and to assess nc886 response to demethylating agents. The effect of nc886 recovery in cell proliferation (in vitro and in vivo) and invasion (in vitro) was evaluated using lentiviral transduced DU145 and LNCaP cell lines. The association between the expression of nc886 and selected genes was analyzed in the TCGA-PRAD cohort.ResultsNc886 promoter methylation increases in tumor vs. normal prostate tissue, as well as in metastatic vs. normal prostate tissue. Additionally, nc886 promoter methylation correlates with prostate cancer clinical staging, including biochemical recurrence, Clinical T-value and Gleason score. Nc886 transcript is downregulated in tumor vs. normal tissue -in agreement with its promoter methylation status- and increases upon demethylating treatment. In functional studies, the overexpression of nc886 in the LNCaP and DU145 cell line leads to a decreased in vitro cell proliferation and invasion, as well as a reduced in vivo cell growth in NUDE-mice tumor xenografts. Finally, nc886 expression associates with the prostate cancer cell cycle progression gene signature in TCGA-PRAD.ConclusionsOur data suggest a tumor suppressor role for nc886 in the prostate, whose expression is epigenetically silenced in cancer leading to an increase in cell proliferation and invasion. Nc886 might hold clinical value in prostate cancer due to its association with clinical parameters and with a clinically validated gene signature.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4049-7) contains supplementary material, which is available to authorized users.

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“…Unlike DNMT1, which preferentially maintains established DNA methylation patterns after replication, DNMT3A and DNMT3B play a critical role in the de novo DNA methylation process [38]. DNMT dysregulation has been frequently reported in malignant tumors, including leukemia, prostate cancer, and gastric cancer [39][40][41]. However, elucidation of the role of dysregulated DNMTs in ovarian carcinogenesis is in its infancy.…”

Section: Discussionmentioning

confidence: 99%

A Double-Negative Feedback Interaction between MicroRNA-29b and DNMT3A/3B Contributes to Ovarian Cancer Progression

Teng

Zuo

Hou

et al. 2016

Cell Physiol Biochem

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Background: Epigenetic abnormalities are increasingly observed in multiple malignancies, including epithelial ovarian cancer (EOC), and their effects can be significantly counteracted by tumor-suppressor microRNAs, namely epi-miRNAs. Here, we investigated the role of miR-29b, a well-established epi-miRNA, in the DNA methylation regulation of EOC cells. Methods: The correlation between miR-29b and DNMT3A/3B expression was evaluated by RT-qPCR, western blotting and immunohistochemical analysis. The functional roles of miR-29b and DNMT3A/3B were tested by anti-miRs and microRNA precursors. A luciferase reporter assay was employed to detect the direct binding of miR-29b to DNMT3A/3B 3′ UTRs. Co-IP was utilized for investigating Id-1 binding activity. Results: miR-29b was negatively correlated with DNMT3A/3B expression at the cellular/histological levels. miR-29b silencing was correlated with increased DNMT3A/3B levels, whereasmiR-29b over-expression caused DNMT3A/3B down-regulation. Luciferase reporter assays confirmed that the miR-29b-mediated downregulation of DNMT3A/3Boccurred through the direct targeting of theirmRNAs'3'-UTRs,whereasBGS assays found that DNMT3A/3B knockdown increased miR-29b expression via CpG island promoter hypomethylation, thus suggesting a crucial crosstalk betweenmiR-29b and DNMT3A/3B via a double-negative feedback loop. Co-IP assay confirmed direct binding between DNMT3A and Id-1. Conclusion: Taken together, our study sheds light on a novel epigenetic circuitry regulating EOC progression and may provide novel options for miR-29b-based epi-therapeutic approaches for future EOC treatment.Y. Teng and X. Zuo and M. Hou contributed equally to this article.

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Multi-target siRNA based on DNMT3A/B homologous conserved region influences cell cycle and apoptosis of human prostate cancer cell line TSU-PR1

Cited by 8 publications

References 24 publications

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

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

Nc886 is epigenetically repressed in prostate cancer and acts as a tumor suppressor through the inhibition of cell growth

A Double-Negative Feedback Interaction between MicroRNA-29b and DNMT3A/3B Contributes to Ovarian Cancer Progression

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