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The oncoprotein HBXIP competitively binds KEAP1 to activate NRF2 and enhance breast cancer cell growth and metastasis

Oncogene volume 38, pages 4028–4046 (2019)Cite this article

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Abstract

The nuclear factor E2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling cascades is a key transcriptional pathway governing cellular oxidative stress and tumor development. Mammalian hepatitis B X-interacting protein (HBXIP) has critical roles in modulating cancer malignance and tumor progression. However, whether HBXIP interacts with KEAP1 and NRF2 is unclear. Here, we found that HBXIP can effectually compete with NRF2 for binding with KEAP1 protein via its highly conserved GLNLG motif. The HBXIP-mediated reduction in NRF2-KEAP1 complexes promotes NRF2 accumulation and nuclear entry, which facilities the activation of antioxidant response element (ARE)-dependent signaling cascades, thereby reducing the accumulation of endogenous cellular reactive oxygen species (ROS). We also found a strong positive correlation between HBXIP expression and NRF2 expression in breast cancer cells, tissue microarrays and clinical breast cancer tissues. Furthermore, this positive correlation was further confirmed via analysis of 1905 clinical cases of breast carcinoma provided by the cancer genomics database cBioPortal. Strikingly, disrupting the HBXIP-KEAP1 axis via mutating the GLNLG motif of HBXIP leads to potent inhibition of the malignancy of breast carcinoma both in vivo and in vitro. Our findings broaden our understanding of HBXIP as a modulation factor of cellular oxidative stress and address a novel regulatory mechanism governing redox homeostasis and the progression of breast carcinoma.

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Acknowledgements

This project was supported by grants from the National Natural Scientific Foundation (No. 81602428), the Colleges and Universities in Hebei Province Science and Technology Research Project (No. QN2016020), and the Science and Technology Research and Developmental Guidance Program of Shijiazhuang City (No. 171201073A). The authors sincerely thank Dr. Lihong Ye for providing mouse model for this study.

Funding

This project was supported by grants from the National Natural Scientific Foundation (No. 81602428), the Colleges and Universities in Hebei Province Science and Technology Research Project (No. QN2016020), and the Science and Technology Research and Developmental Guidance Program of Shijiazhuang City (No. 171201073 A)

Author contributions

XZ conceived and coordinated the study and wrote the paper. XZ, CZ, and ZW performed and analyzed the experiments shown in Figs. 1–2 and 4–8. XG performed and analyzed the experiments shown in Fig. 3. WZ provided technical assistance and contributed to the preparation of the figures. All authors reviewed the results and approved the final version of the manuscript.

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Authors and Affiliations

  1. Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, 050018, Shijiazhuang, China

    Xiao-Lei Zhou, Chong-Yue Zhu, Zhi-Gang Wu & Wei Zou

  2. Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

    Xin Guo

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Correspondence to Xiao-Lei Zhou.

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Zhou, XL., Zhu, CY., Wu, ZG. et al. The oncoprotein HBXIP competitively binds KEAP1 to activate NRF2 and enhance breast cancer cell growth and metastasis. Oncogene 38, 4028–4046 (2019). https://doi.org/10.1038/s41388-019-0698-5

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