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p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A

Oncogene volume 35, pages 1399–1410 (2016)Cite this article

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Abstract

Dysregulation of lipid metabolism is common in breast cancer. However, the underlying mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of breast cancer is poorly understood. Here, we show that the nuclear protein p54nrb/Nono is highly expressed in breast cancer tissues as compared with the adjacent normal tissues in human patients. To determine the functions of p54nrb in breast cancer, we performed a biochemical screen and identified SREBP-1a, a master activator for genes involved in lipid biosynthesis, as a novel interacting protein of p54nrb. In human breast cancer tissues, the levels of p54nrb and SREBP-1a proteins were positively correlated with each other. Our biochemical analyses showed that the conserved Y267 residue of p54nrb was required for its binding to the nuclear form of SREBP-1a. Interestingly, p54nrb binding to nuclear SREBP-1a caused an increase of nuclear SREBP-1a protein stability. As a result, p54nrb stimulates SREBP-1-meidated transcription of lipogenic genes and lipid production in breast cancer cells. Moreover, both p54nrb and SREBP-1a were required for breast cancer cell growth in vitro, and p54nrb binding to nuclear SREBP-1a was also critical for breast tumor development in vivo. Together, we conclude that p54nrb is a novel regulator of SREBP-1a in the nucleus, and our data suggest that p54nrb regulation of SREBP-1a supports the increased cellular demand of lipids for breast cancer growth. Thus, the SREBP pathway may represent a novel target for treating breast cancer.

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Acknowledgements

The study was supported by research grants from ‘973‘ Project (No. 2012CB932604), New Drug Discovery Project (No. 2012ZX09506-001-005), Shanghai First-class Discipline (Medical technology), National Natural Science Foundation of China (No. 81372195, 81471685 and 81471687), Shanghai Pujiang Program (No. 13PJ1406000), Science and Technology Commission of Shanghai Municipality (No. 134119a5600), Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No. 1410000157) and Shanghai Municipal Commission of Health and Family Planning (XYQ2013109). FY was supported by NIH R01 (DK093623).

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  1. Z Zhu and X Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Z Zhu, X Zhao, L Zhao, L Liu, J Li, J Wu, G Huang & J Liu

  2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    H Yang & G Huang

  3. Department of Medicine and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA

    F Yang

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Correspondence to G Huang or J Liu.

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Zhu, Z., Zhao, X., Zhao, L. et al. p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A. Oncogene 35, 1399–1410 (2016). https://doi.org/10.1038/onc.2015.197

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