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.
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This work was supported by grants from the National Basic Research Program of China (973 Program No. 2015CB553905), the National Natural Scientific Foundation of China (Nos. 81372186, 31670771), the Fundamental Research Funds for the Central Universities, Project of Prevention and Control of Key Chronic Non Infectious Diseases (No. 2016YFC1303401), CAMS Innovation Fund for Medical Sciences (CIFMS, 2017-I2M-3-019 and 2016-I2M-1-017), the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities (No. 2017310027), the Tianjin Science and Technology Support Plan Project (TJKJZC, 14ZCZDSY00001).
HL, ZW, MJ, YS, X-lC, and QL performed the experiments. HL, R-pF, HS, and KY carried out the data analysis. HL, S-jF, W-yZ, L-hY designed the study. S-jF, W-yZ, and L-hY supervised the study. HL, S-jF, W-yZ, and L-hY wrote the manuscript with input from all authors.
The authors declare no competing interests.
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Journal of Experimental & Clinical Cancer Research (2019)