3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation

Peng, Xiaoli; Chang, Hui; Chen, Junli; Zhang, Qianyong; Yu, Xiaoping; Mi, Mantian

doi:10.1186/s12885-017-3638-1

Cited by 20 publications

(11 citation statements)

References 40 publications

(44 reference statements)

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“…Aberrant expressions of miRNAs are involved in the regulation of stemness in various cancers by controlling stemness-related gene expressions [10, 11, 14, 34–40]. miR-34a has been recognized as a tumor-suppressive miRNA and reduced carcinogenesis in a variety of cancers, including OS [30–33]. Underexpression of miR-34a has been implicated in maintaining the stemness of CSLCs [14, 15], especially in OS cells [10, 11].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, tumor-suppressive miRNAs could be silenced by DNA hypermethylation in the promoter regions [26–29]. Recent studies showed that miR-34a promoter hypermethylation led to epigenetic inactivation [30–33]. Considering the regulation of stemness of OSLCs by miR-34a [10, 11], we hypothesized that it may be possible to repress the stemness by upregulating miR-34a through inactivating DNMT1 in human OS cells and their derived OSLCs.…”

Section: Introductionmentioning

confidence: 99%

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The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells

Liang

Wang

et al. 2019

Stem Cells International

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The DNA methyltransferase 1 (DNMT1)/miR-34a axis promoted carcinogenesis of various types of cancers. However, no literature reported its contribution to the stemness of osteosarcoma cancer stem-like cells (OSLCs). We sought to determine whether the DNMT1/miR-34a axis facilitates the stemness of OSLCs. We here revealed the higher DNMT1 activity and expression, lower miR-34a expression with high methylation of its promoter, and stronger stemness of OSLCs, as manifested by elevated sphere and colony formation capacities; CD133, CD44, ABCG2, Bmi1, Sox2, and Oct4 protein amounts in vitro; and carcinogenicity in a nude mouse xenograft model, when compared to the parental U2OS cells. 5-Azacytidine (Aza-dC) repressed DNMT1 activation and upregulated miR-34a expression by promoter demethylation and suppressed the stemness of OSLCs in a dose-dependent manner. DNMT1 knockdown increased miR-34a and reduced the stemness of OSLCs. Transfection with a miR-34a mimic repressed the stemness of OSLCs but did not alter DNMT1 activity and expression. Conversely, DNMT1 overexpression declined miR-34a levels, promoting the stemness of U2OS cells. Transfection with a miR-34a inhibitor enhanced the stemness of U2OS cells, without affecting the DNMT1 activity and expression. Importantly, reexpression of miR-34a could rescue the effects of DNMT1 overexpression on miR-34a inhibition as well as the stemness promotion without affecting the activity and expression of DNMT1. Our results revealed that aberrant activation of DNMT1 caused promoter methylation of miR-34a, leading to miR-34a underexpression, and the role of the DNMT1/miR-34a axis in promoting and sustaining the stemness of OSLCs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells

Liang

Wang

et al. 2019

Stem Cells International

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“… Zhao et al (2017) also demonstrated that combined miR-34a mimics and EGFR-TKIs synergistically sensitized both EGFR wild-type and mutant NSCLC cells. The hypermethylation of miR-34a promotor was mediated by several DNA methyltransferases (Dnmts), including Dnmt1, Dnmt2, and Dnmt3a ( Peng et al, 2015 , 2017 ; Wang et al, 2016 ; Lewinska et al, 2018 ). Here, we show MIAT binds to the miR-34a promotor, and recruits Dnmt3a to methylate the promotor, leading to silencing of miR-34a expression.…”

Section: Discussionmentioning

confidence: 99%

Silencing of Long Non-coding RNA MIAT Sensitizes Lung Cancer Cells to Gefitinib by Epigenetically Regulating miR-34a

Luo

et al. 2018

Front. Pharmacol.

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Long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) was recently identified as oncogene in several cancers. However, the role of MIAT on acquired resistance in lung cancer and the underlying mechanisms remain unclear. Here, we showed that the expression of MIAT in lung cancer tissues was upregulated compared with adjacent tissues. LncRNA MIAT expression was associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. Univariate analysis and multivariate analysis revealed that the lncRNA MIAT to be an independent factor for predicating the prognosis of lung cancer patients. Low lncRNA MIAT have longer overall survival time and progression-free survival time than patients with high lncRNA MIAT expression. Moreover, the knockdown of MIAT significantly sensitized PC9 and gefitinib-resistant PC9 cells to gefitinib in vitro and in vivo, and increased the expression of miR-34a and inactivated PI3K/Akt signaling. MIAT interacted with miR-34a and epigenetically controlled the miR-34a expression by hyper-methylating its promotor. Taken together, our findings demonstrated that knockdown of MIAT by siRNA enhances lung cancer cells to gefitinib through the PI3K/Akt signaling pathway by epigenetically regulating miR-34a. Thus, MIAT may be a useful prognostic marker and therapeutic target for lung cancer patients.

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“…DNMT1 is important in maintaining cancer stem cells since upregulated miR-34a associated with DNMT1 inhibition can reduce the viability of liver cancer cells [27]. We therefore initially explored whether CD133 + spheres from MHCC97H cells used as LCSCs are involved in DNMT activation and methylation silencing of miR-34a.…”

Section: Dnmt1 Activation Promotes the Stemness Of Lcscsmentioning

confidence: 99%

The DNMT1/miR-34a/FOXM1 Axis Contributes to Stemness of Liver Cancer Cells

Cao

Liu

Cao

et al. 2020

Journal of Oncology

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Background. Whether DNA methyltransferase 1 (DNMT1)/miR-34a/FoxM1 signaling promotes the stemness of liver cancer stem cells (LCSCs) remains unclear. This study aimed to assess whether methylation-based silencing of miR-34a by DNMT1 contributes to stemness features via FoxM1 upregulation in LCSCs. Methods. The CD133+ subgroup of MHCC97H cells sorted by MACS was used as LCSCs. DNMT1, BMI1, SOX2, and OCT4 mRNA levels, and miR-34a amounts were determined by qRT-PCR. DNMT1, CD44, and FoxM1 proteins were analyzed by immunoblot. Sphere and colony formation abilities were detected by respective assays. CD133+ cell percentages were assessed by flow cytometry. In vivo oncogenicity was evaluated using a tumor xenograft model in mice. The effects of DNMT1/miR-34a signaling on the stemness of LCSCs were examined by knockdown or overexpression of DNMT1 and/or transfection of miR-34a mimic or inhibitor using lentivirus-delivery systems. FoxM1 association with miR-34a was detected by a reporter assay. Results. We here showed that LCSCs exhibited elevated DNMT1 activity and expression, lower miR-34a expression with higher promoter methylation, and stronger stemness, compared with the parental liver cancer cells. DNMT1 knockdown repressed DNMT1, increased miR-34a amounts by promoter demethylation, and reduced stemness in LCSCs, whereas DNMT1 overexpression had the opposite effects in liver cancer cells. Transfection with miR-34a mimic repressed the stemness of LCSCs, while miR-34a inhibitor significantly downregulated miR-34a and enhanced stemness, without affecting DNMT1 in liver cancer cells. MiR-34a mimic rescued the effects of DNMT1 overexpression on the stemness of LCSCs, without affecting DNMT1 expression. Finally, FOXM1 was identified as a direct target by miR-34a in LCSCs. Conclusions. We revealed that aberrant activation of DNMT1 causes miR-34a promoter methylation and suppression, leading to FoxM1 upregulation by disinhibition and promotion of LCSC stemness. These findings suggest that blockage of DNMT1/miR-34a-mediated FOXM1 upregulation might suppress liver cancer by targeting LCSCs.

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3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation

Cited by 20 publications

References 40 publications

The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells

The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells

Silencing of Long Non-coding RNA MIAT Sensitizes Lung Cancer Cells to Gefitinib by Epigenetically Regulating miR-34a

The DNMT1/miR-34a/FOXM1 Axis Contributes to Stemness of Liver Cancer Cells

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