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A TGF-β-MTA1-SOX4-EZH2 signaling axis drives epithelial–mesenchymal transition in tumor metastasis

Oncogene volume 39, pages 2125–2139 (2020)Cite this article

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Abstract

MTA1, SOX4, EZH2, and TGF-β are all potent inducers of epithelial–mesenchymal transition (EMT) in cancer; however, the signaling relationship among these molecules in EMT is poorly understood. Here, we investigated the function of MTA1 in cancer cells and demonstrated that MTA1 overexpression efficiently activates EMT. This activation resulted in a significant increase in the migratory and invasive properties of three different cancer cell lines through a common mechanism involving SOX4 activation, screened from a gene expression profiling analysis. We showed that both SOX4 and MTA1 are induced by TGF-β and both are indispensable for TGF-β-mediated EMT. Further investigation identified that MTA1 acts upstream of SOX4 in the TGF-β pathway, emphasizing a TGF-β-MTA1-SOX4 signaling axis in EMT induction. The histone methyltransferase EZH2, a component of the polycomb (PcG) repressive complex 2 (PRC2), was identified as a critical responsive gene of the TGF-β-MTA1-SOX4 signaling in three different epithelial cancer cell lines, suggesting that this signaling acts broadly in cancer cells in vitro. The MTA1-SOX4-EZH2 signaling cascade was further verified in TCGA pan-cancer patient samples and in a colon cancer cDNA microarray, and activation of genes in this signaling pathway predicted an unfavorable prognosis in colon cancer patients. Collectively, our data uncover a SOX4-dependent EMT-inducing mechanism underlying MTA1-driven cancer metastasis and suggest a widespread TGF-β-MTA1-SOX4-EZH2 signaling axis that drives EMT in various cancers. We propose that this signaling may be used as a common therapeutic target to control epithelial cancer metastasis.

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Fig. 1: MTA1 induces EMT to enhance cancer cell migration and invasion.
Fig. 2: MTA1 increases SOX4 expression during EMT induction.
Fig. 3: MTA1 activates EMT in a SOX4-dependent manner.
Fig. 4: SOX4 is indispensable for TGF-β-induced EMT.
Fig. 5: MTA1 is activated by TGF-β and is indispensable for TGF-β-induced EMT.
Fig. 6: MTA1 mediates SOX4 induction by TGF-β.
Fig. 7: EZH2 is a downstream target of TGF-β-MTA1-SOX4 signaling in cancer.
Fig. 8: Schematic diagram showing the TGF-β-MTA1-SOX4-EZH2 signaling axis in promoting EMT and cancer metastasis.

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Acknowledgements

This work was financially supported by grants from the National Natural Science Foundation of China (Nos 81502384, 81572842, 81672459, 81872280, 81672338), the National Basic Research Program of China (973 Program) (No. 2015CB553904), the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2016-I2M-1-001, 2019-I2M-1-003), the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2017PT31029), the Open Issue of State Key Laboratory of Molecular Oncology (No. SKL-KF-2017-16), the Independent Issue of State Key Laboratory of Molecular Oncology (No. SKL-2017-16) and Dalian Science and Technology Project (No. 2015E12SF117).

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  1. These authors contributed equally: Lina Li, Jian Liu, Hongsheng Xue, Chunxiao Li

Authors and Affiliations

  1. Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China

    Lina Li, Jian Liu & Tao Wen

  2. Department of Thoracic Surgery, the Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China

    Hongsheng Xue

  3. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Chunxiao Li, Yantong Zhou, Ting Wang, Haijuan Wang & Haili Qian

  4. Department of gynaecology and obstetrics, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Qun Liu

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Li, L., Liu, J., Xue, H. et al. A TGF-β-MTA1-SOX4-EZH2 signaling axis drives epithelial–mesenchymal transition in tumor metastasis. Oncogene 39, 2125–2139 (2020). https://doi.org/10.1038/s41388-019-1132-8

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