The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells

Sorianello, Eleonora; Soriano, Francesc X.; Fernández-Pascual, Sergio; Sancho, Ana; Naón, Déborah; Vila-Caballer, Marian; González-Navarro, Herminia; Portugal, José; Andrés, Vicente; Palacı́n, Manuel; Zorzano, António

doi:10.1093/cvr/cvs006

Cited by 26 publications

(30 citation statements)

References 31 publications

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“…In the present study, the anti-proliferation, anti-migration and anti-invasion effects of Mfn2 were confirmed in breast cancer cells. The results are consistent with previous studies in VSMCs (3) and in various types of cancer, including breast cancer (18,37) gastric cancer (18), urinary bladder carcinoma (38) and hepatocellular carcinoma (20,21,23) and lung adenocarcinoma (5,8,24,(38)(39)(40)(41). However, tumor-promoting functions of Mfn2 in lung adenocarcinoma have also been reported (42,43).…”

Section: Discussionsupporting

confidence: 92%

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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: Discussionsupporting

confidence: 92%

“…However, Sorianello et al (23) reported that the promoter of Mfn2 was unmethylated in rat insulinoma and hepatoma cells, as analyzed by bisulfite sequencing. It is speculated that Mfn2 expression is regulated via different mechanisms which vary between species and tissues.…”

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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“…Sp1 is also a key factor in maintaining basal mitofusin-2 (Mfn2) transcription in vascular smooth muscle cells. Because of the antiproliferative actions of Mfn2, Sp1-induced Mfn2 transcription is considered a mechanism for the prevention of proliferation of the vascular smooth muscle cells (Sorianello, et al, 2012).…”

Section: Sp1 Is Involved In Cell Growth and Tumorigenesismentioning

confidence: 99%

Sp1 transcription factor: A long-standing target in cancer chemotherapy

Vizcaíno

Mansilla

Portugal

2015

Pharmacology & Therapeutics

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329

244

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“…Although we previously showed that GLP-1 induced CREB phosphorylation [12], we were unable to demonstrate that CREB was responsible for Mfn2 up-regulation. Analysis of human and rat Mfn2 promoters showed that in VSMC, Mfn2 expression is regulated by Sp1 [31]. Moreover, PKA activation was reported to regulate Sp1 activity [32].…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation

Torres

Morales

García-Miguel

et al. 2016

Biochemical Pharmacology

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Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicine for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism.

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The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells

Abstract: Sp1 is a key factor in maintaining basal Mfn2 transcription in VSMCs. Given the anti-proliferative actions of Mfn2, Sp1-induced Mfn2 transcription may represent a mechanism for prevention of VSMC proliferation and neointimal lesion and development.

Cited by 26 publications

References 31 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

Sp1 transcription factor: A long-standing target in cancer chemotherapy

Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation

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