DNA Methylation-mediated Repression of miR-941 Enhances Lysine (K)-specific Demethylase 6B Expression in Hepatoma Cells

Zhang, Pei Pei; Wang, Xiang Ling; Zhao, Wei; Qi, Bing; Yang, Qian; Wan, Hai Ying; Shuang, Ze Yu; Liu, Min; Li, Xin; Li, Shengping; Tang, Hua

doi:10.1074/jbc.m114.567818

Cited by 45 publications

(34 citation statements)

References 49 publications

(43 reference statements)

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“…Furthermore, KDM6B gene expression was down-regulated with excess SAH, suggesting that a feedback mechanism may be triggered due to lack of substrate. Interestingly, it was recently reported in cancer cell lines that JMJD3 suppression can be mediated by miR-941, which is upregulated with DNA hypomethylation [56]. Similarly, EZH2 expression has been shown to be suppressed by microRNAs that may normally be transcriptionally repressed by DNA methylation [57].…”

Section: Discussionmentioning

confidence: 99%

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

Barroso

Kao

Blom

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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S-Adenosylhomocysteine (SAH) can induce endothelial dysfunction and activation, contributing to atherogenesis; however, its role in the activation of the inflammatory mediator NFkB has not been explored. Our aim was to determine the role of NFkB in SAH-induced activation of endothelial cells. Furthermore, we examined whether SAH, as a potent inhibitor of S-adenosylmethionine-dependent methyltransferases, suppresses the function of EZH2 methyltransferase to contribute to SAH-induced endothelial cell activation. We found that excess SAH increases the expression of adhesion molecules and cytokines in human coronary artery endothelial cells. Importantly, this up-regulation was suppressed in cells expressing a dominant negative form of the NFkB inhibitor, IkB. Moreover, SAH accumulation triggers the activation of both the canonical and non-canonical NFkB pathways, decreases EZH2, and reduces histone 3 lysine 27 trimethylation. EZH2 knockdown recapitulated the effects of excess SAH on endothelial activation, i.e., it induced NFkB activation and the subsequent up-regulation of adhesion molecules and cytokines. Our findings suggest that suppression of the epigenetic regulator EZH2 by excess SAH may contribute to NFkB activation and the consequent vascular inflammatory response. These studies unveil new targets of SAH regulation, demonstrating that EZH2 suppression and NFkB activation mediated by SAH accumulation may contribute to its adverse effects in the vasculature.

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Section: Discussionmentioning

confidence: 99%

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

Barroso

Kao

Blom

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…At the same time, miRNAs which act as tumor-suppressor genes and oncogenes are also subjected to regulation of epigenetics, such as DNA methylation status of promoter gene [10,17,12]. Various oncogenic or tumor-suppressor miRNAs are now known to be regulated via DNA methylation status of the miRNA promoter region [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma

et al. 2014

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Aberrant microRNA (miRNA) expression has been widely recognized to play an extremely important role in several cancers, including hepatocellular carcinoma (HCC). According to the previous studies, abnormal miR-106a expression was closely related to various cancer occurrences. However, the miR-106a expression in HCC remains unclear. In our study, we firstly detected the miR-106a expression levels in 36 pairs of HCC tissues. The results showed that miR-106a expression in HCC tissues was apparently higher than the level in the adjacent tissues. Then, we used quantitative real-time PCR (qPCR) and BSP to analyze miR-106a expression and promoter methylation in HCC cell lines. There came to a conclusion that the methylation status of the miR-106a promoter region was inversely correlated with the expression of miR-106a. After prediction with online software, we further used dual-luciferase reporter gene assay to ensure that TP53INP1 and CDKN1A might be the direct targets of miR-106a. At last, we explored the functions of miR-106a in HCC cells in vitro. Our results manifested that high-miR-106a cell line had stronger invasiveness, faster cell cycle progression, and more resistance to apoptosis compared with the low-miR-106a cell line. Therefore, our study suggested that upregulated expression of miR-106a by its promoter hypomethylation might contribute to the progression of HCC, which might be considered as a potentially effective biomarker and therapeutic approach in the future.

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“…In addition, overexpression of JMJD3 in glioblastoma stem cells attenuates their proliferation by activating the p53 pathway (27), suggesting its antitumorigenic roles. By contrast, JMJD3 promotes T-ALL and hepatoma growth by enhancing their proliferation (22,23). However, the role of JMJD3 in the context of melanoma progression and metastasis remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, recent studies have suggested that JMJD3 plays both tumorsuppressive and -promoting roles in a tumor type-specific manner (22)(23)(24)(25)(26)(27)(28). For example, oncogene-induced expression of JMJD3 in fibroblasts causes senescence by stimulating expression of tumor suppressors, including p14 ARF and p16 INK4A (25,26).…”

Section: Introductionmentioning

confidence: 99%

H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis

et al. 2016

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Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-kB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment.

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DNA Methylation-mediated Repression of miR-941 Enhances Lysine (K)-specific Demethylase 6B Expression in Hepatoma Cells

Cited by 45 publications

References 49 publications

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma

H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis

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