Article

The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways

Authors: Hang Li1,2, Zhen Wang1, Mian Jiang2, Run-ping Fang1, Hui Shi1, Yu Shen1, Xiao-li Cai1, Qian Liu1, Kai Ye1, Sai-jun Fan2, Wei-ying Zhang1, Li-hong Ye1
1 State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China
2 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
Correspondence to: Sai-jun Fan: fansaijun@irm-cams.ac.cn, Wei-ying Zhang: zhwybao@nankai.edu.cn, Li-hong Ye: yelihong@nankai.edu.cn,
DOI: 10.1038/s41401-018-0034-6
Received: 26 January 2018
Accepted: 27 March 2018
Advance online: 4 September 2018

Abstract

Mammalian hepatitis B X-interacting protein (HBXIP) is an 18-kDa protein that regulates a large number of transcription factors such as TF-IID, E2F1, SP1, STAT3, c-Myc, and LXR by serving as an oncogenic transcription coactivator and plays an important role in the development of breast cancer. We previously showed that HBXIP as an oncoprotein could enhance the promoter activity of MDM2 through coactivating p53, promoting the MDM2 transcription in breast cancer. In this study we investigated the molecular mechanisms underlying the modulation of MDM2/p53 interaction by HBXIP in human breast cancer MCF-7 cells in vitro and in vivo. We showed that HBXIP could up-regulate MDM2 through inducing DNA methylation of miR-18b, thus suppressing the miR-18b expression, leading to the attenuation of p53 in breast cancer cells. In addition, HBXIP could promote the phosphorylation of MDM2 by increasing the level of pAKT and bind to pMDM2, subsequently enhancing the interaction between MDM2 and p53 for the down-regulation of p53 in breast cancer cells. In MCF-7 breast cancer xenograft nude mice, we also observed that overexpression of HBXIP promoted breast cancer growth through the miR-18b/MDM2 and pAKT/MDM2 pathways. In conclusion, oncoprotein HBXIP suppresses miR-18b to elevate MDM2 and activates pAKT to phosphorylate MDM2 for enhancing the interaction between MDM2 and p53, leading to p53 degradation in promotion of breast cancer growth. Our findings shed light on a novel mechanism of p53 down-regulation during the development of breast cancer.
Keywords: HBXIP; p53; MDM2; miR-18b; pAKT; human breast cancer; cell proliferation; MCF-7 cells; cancer xenograft nude mice.

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