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

Li,Yufeng; Dong,Wenyue; Shan,Xijin; Hong,Hui; Liu,Yan; Liu,Yankun; Liu,Xiaohui; Zhang,Xiaojun; Zhang,Jinghua

doi:10.3892/ol.2018.8314

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

Authors:
- Yufeng Li
- Wenyue Dong
- Xijin Shan
- Hui Hong
- Yan Liu
- Yankun Liu
- Xiaohui Liu
- Xiaojun Zhang
- Jinghua Zhang
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Affiliations: The Cancer Institute, Affiliated Tangshan People's Hospital of North China University of Science and Technology, Tangshan, Hebei 063001, P.R. China, Department of Anesthesiology, Affiliated Tangshan People's Hospital of North China University of Science and Technology, Tangshan, Hebei 063001, P.R. China, Department of Surgery, Rizhao Port Hospital, Rizhao, Shandong 276800, P.R. China, Department of Head, Neck and Breast Surgery, Shangrao People's Hospital, Shangrao, Jiangxi 334000, P.R. China, Department of Bioengineering, College of Life Sciences, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China, Department of Thoracic Surgery, Affiliated Tangshan People's Hospital of North China University of Science and Technology, Tangshan, Hebei 063001, P.R. China, Department of Internal Medicine, Affiliated Zunhua People's Hospital of North China University of Science and Technology, Zunhua, Hebei 064200, P.R. China
Published online on: March 21, 2018 https://doi.org/10.3892/ol.2018.8314
Pages: 8011-8018

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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 (Mfn2ΔRas) and protein kinase A (PKA) phosphorylation site (Mfn2ΔPKA) 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 P21Ras binding site and PKA phosphorylation.

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