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C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake

Oncogene volume 39, pages 833–848 (2020)Cite this article

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Abstract

Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-β1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis.

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Acknowledgements

We are thankful to Dr Yan Lu (Zhongshan Hospital, Shanghai) and Zhenfei Li (SIBS, Shanghai) for reading the paper and for discussions throughout the project. This project is supported by funds from the National Natural Science Foundation of China (31770840 to XM, 31800989 to LX, 81902980 to DW, and 81502480 to XC), Shanghai Pujiang Program (17PJ1402600 to XM and 17PJ1402700 to LX), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (TP2017042 to XM), Shanghai Young Top Notch Talents (to XM), the China Postdoctoral Science Foundation (2017M611499 to DW), and ECNU public platform for Innovation (011).

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  1. These authors contributed equally: Dongmei Wang, Xinghua Cheng

Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong-Chuan Road, 200241, Shanghai, China

    Dongmei Wang, Yu Li, Mingwei Guo, Wenjun Zhao, Jin Qiu, Ying Zheng, Meiyao Meng, Xiaodan Ping, Xin Chen, Jian Luo, Xinran Ma & Lingyan Xu

  2. Shanghai Pulmonary Tumor Medical Center, Department of Oncology, Shanghai Chest Hospital, Affiliated to Shanghai Jiao-Tong University, 241 West Huai-Hai Road, 200030, Shanghai, China

    Xinghua Cheng & Qingquan Luo

  3. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, 200025, Shanghai, China

    Shu Wang, Xinran Ma & Lingyan Xu

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Correspondence to Xinran Ma or Lingyan Xu.

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Ethical approval

All animal experiments were performed in accordance with a protocol approved by the ethics committee of Animal experiments of East China Normal University (Approval Number: m20170208). The lung cancer tissues and adjacent normal tissues were collected from Shanghai Chest Hospital, Affiliated to Shanghai Jiao-Tong University and the patients were informed and agreed to this experiments.

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Wang, D., Cheng, X., Li, Y. et al. C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake. Oncogene 39, 833–848 (2020). https://doi.org/10.1038/s41388-019-1015-z

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