Methylation of specific CpG sites in the P2 promoter of<i>parathyroid hormone-related protein</i>determines the invasive potential of breast cancer cell lines

Tost, Jörg; Hamzaoui, Hinda; Busato, Florence; Neyret, Aymeric; Dupont, Jean‐Michel; Bouizar, Zhor

doi:10.4161/epi.6.8.16077

Cited by 9 publications

(6 citation statements)

References 32 publications

(58 reference statements)

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“…This suggests that Mfn2 hypoexpression in breast cancer is at least partially attributable to hypermethylaton of its promoter. Although 5-aza-CdR can rescue the expression of tumor suppressor genes by demethylating their promoter CpG sites (24)(25)(26)(27)(28)(29)(30)(31), its clinical anti-tumor applications are limited due to lack of gene specificity. Furthermore, it was reported that Mfn2 is a direct target of miR-761 and upregulation of Mfn2 expression by inhibiting miR-761 repressed hepatocarcinoma growth and metastasis (32).…”

Section: Discussionmentioning

confidence: 99%

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Dong

Shan

et al. 2018

Oncol Lett

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Abstract. Mitofusin 2 (Mfn2) is expressed in numerous human tissues and serves a pivotal role in cell proliferation. However, Mfn2 is considered as an anti-tumor gene, and is silenced in human malignant tumors, including those of breast cancer. However, the mechanisms contributing to Mfn2 silencing and the mechanism of its anti-tumor function in breast cancer remain unclear. In the present study, hypoexpression of Mfn2, and hypermethylation of its promoter, was confirmed in human breast cancer cells and in breast cancer tissues by reverse transcription-quantitative polymerase chain reaction (PCR) and methylation specific PCR, respectively. Chemical demethylation treatment with 5-aza-2'-deoxycytidine upregulated the mRNA expression level of Mfn2 in MCF-7 cells in a dose-dependent manner. In addition, overexpression of Mfn2 repressed the proliferation, migration and invasion of MCF-7 cells, mediated by inhibition of the Ras-extracellular signal-regulated kinase (ERK)1/2 signaling pathway. However, overexpression of Mfn2 with deletion of the p21Ras motif (Mfn2 ΔRas ) and protein kinase A (PKA) phosphorylation site (Mfn2 ΔPKA ) partially reduced the anti-tumor function of Mfn2, and inhibited the Ras-ERK1/2 signaling pathway. Taken together, the present study confirmed the anti-tumor effects of Mfn2 in human breast cancer and clarified that the mechanism of its anti-tumor functions includes promoter DNA methylation, the P21 Ras binding site and PKA phosphorylation.

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Section: Discussionmentioning

confidence: 99%

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Dong

Shan

et al. 2018

Oncol Lett

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“…The treatment of DNA methyltransferase inhibitors, such as 5-aza-dC, to evaluate the DNA methylation on selected genes has been widely accepted, and it can induce the re-expression of tumor suppressor genes by demethylating promoter CpG sites [30]–[31]. In this study, after treatment with 5′-azaC for 7 days, an induction of heparanase mRNA expression and protein abundance in MCF-7 cells resulted in an increase in invasive capacity of these cells.…”

Section: Discussionmentioning

confidence: 84%

DNA Methylation of Heparanase Promoter Influences Its Expression and Associated with the Progression of Human Breast Cancer

Jiao

Shi-yu

et al. 2014

PLoS ONE

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Heparanase promotes tumor invasion and metastasis in several malignancies including breast cancer. However, the roles and regulation mechanisms of heparanase during breast cancer progression are still not fully understood. The aim of this study is to determine the differential regulation of heparanase gene expression in specific stages of breast cancer by DNA methylation. We detected levels of heparanase expression and DNA methylation patterns of its promoter in breast cancer cell lines (MCF-7 and MDA-MB-435) and clinical tissues, respectively. It has been observed that heparanase is highly expressed in the invasive MDA-MB-435 cells with low methylation modification in the heparanase promoter. In contrast, lower expression of heparanase in MCF-7 cells is accompanied by higher methylation in the promoter. Treatment of MCF-7 cells with 5-aza-2′-deoxycytidine (5-aza-dC), a potent demethylating agent, results in induction of heparanase expression and higher invasion potential in vitro and leads to an advantage of tumor formation in vivo. In 54 tissue samples, cancer samples at late stages (stage IV) showed the highest heparanase expression accomplished by little DNA methylation. On the contrary, methylation prevalence is highest in normal tissue and inversely correlated with heparanase expression. A significant correlation between DNA methylation and clinical stage was demonstrated (p = 0.012). Collectively, these results demonstrate that DNA methylation play the regulation role in heparanase gene in different stages of breast cancer and present a direct effect on tumor progression.

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“…Results obtained with a human model of mammary epithelial cell lines differing in tumorigenicity and PTHrP expression, have suggested that the methylation status of specific CpG dinucleotides in the P2 promoter is the dominant mechanism involved in silencing of PTHrP expression rather than the overall methylation of the CpG island. Methylation of the PTHrP P2 promoter might represent a potential marker of breast cancer progression and be used to evaluate the metastatic potential of breast tumors [42].…”

Section: Discussionmentioning

confidence: 99%

PTHrP in differentiating human mesenchymal stem cells: Transcript isoform expression, promoter methylation, and protein accumulation

et al. 2013

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Human PTHrP gene displays a complex organization with nine exons producing diverse mRNA variants due to alternative splicing at 5 0 and 3 0 ends and the existence of three different transcriptional promoters (P1, P2 and P3), two of which (P2 and P3) contain CpG islands. It is known that the expression of PTHrP isoforms may be differentially regulated in a developmental stage-and tissue-specific manner. To search for novel molecular markers of stemness/differentiation, here we have examined isoform expression in fat-derived mesenchymal stem cells both maintained in stem conditions and induced toward adipo-and osteogenesis. In addition, the expression of the splicing isoforms derived from P2 and P3 promoters was correlated to the state of methylation of the latter. Moreover, we also performed a quantitative evaluation of intracellular and secreted PTHrP protein product in undifferentiated stem cells and in parallel cultures at various differentiation stages. The data obtained indicate that from the stemness condition to that of osteo-and adipo-genic differentiated cells, the expression of isoforms becomes increasingly selective, thereby being a potential gene signature for the monitoring of cell stem or committed/differentiating state and that the switching-off of PTHrP isoform expression is mostly promoter methylation-dependent. Moreover, PTHrP intracellular retention is down-regulated in osteo-differentiating cells whereas the secretion of the protein in the extracellular medium is up-regulated with respect to stem cells, thereby suggesting that these variations of the intracellular and extracellular levels of PTHrP could potentially be enclosed in the list of the available protein signature of osteogenic differentiation. Ó 2013 Published by Elsevier Masson SAS.

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Methylation of specific CpG sites in the P2 promoter ofparathyroid hormone-related proteindetermines the invasive potential of breast cancer cell lines

Cited by 9 publications

References 32 publications

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

DNA Methylation of Heparanase Promoter Influences Its Expression and Associated with the Progression of Human Breast Cancer

PTHrP in differentiating human mesenchymal stem cells: Transcript isoform expression, promoter methylation, and protein accumulation

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