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Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis

Oncogene volume 39, pages 2509–2522 (2020)Cite this article

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Abstract

An increasing number of enzymes involved in serine biosynthesis have been identified and correlated with malignant evolution in various types of cancer. Here we showed that the overexpression of phosphoserine aminotransferase 1 (PSAT1) is widely found in lung cancer tissues compared with nontumor tissues and predicts a poorer prognosis in patients with lung adenocarcinoma. PSAT1 expression was examined in a tissue microarray by immunohistochemistry. The data show that the knockdown of PSAT1 dramatically inhibits the in vitro and in vivo metastatic potential of highly metastatic lung cancer cells; conversely, the enforced expression of exogenous PSAT1 predominantly enhances the metastatic potential of lung cancer cells. Importantly, manipulating PSAT1 expression regulates the in vivo tumor metastatic abilities in lung cancer cells. Adjusting the glucose and glutamine concentrations did not alter the PSAT1-driven cell invasion properties, indicating that this process might not rely on the activation of its enzymatic function. RNA microarray analysis of transcriptional profiling from PSAT1 alternation in CL1-5 and CL1-0 cells demonstrated that interferon regulatory factor 1 (IRF1) acts as a crucial regulator of PSAT1-induced gene expression upon metastatic progression. Decreasing the IRF1-IFIH1 axis compromised the PSAT1-prompted transcriptional reprogramming in cancer cells. Our results identify PSAT1 as a key regulator by a novel PSAT1/IRF1 axis in lung cancer progression, which may serve as a potential biomarker and therapeutic target for the treatment of lung cancer patients.

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Fig. 1: In silico analysis showed that PSAT1 is overexpressed in lung adenocarcinoma patients.
Fig. 2: PSAT1 expression in normal and tumor tissues derived from clinical lung cancer patients.
Fig. 3: Endogenous PSAT1 expression and in vitro cell invasion assay.
Fig. 4: The in vivo lung metastatic colonization assay.
Fig. 5: Characterization of invasion and the serine biosynthetic pathway in lung cancer cell lines.
Fig. 6: PSAT1 suppressed IRF1 activation and downstream targets.
Fig. 7: IRF1- IFNγ pathway triggered upon PSAT1-regulating lung cancer cell metastasis.

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Acknowledgements

This study is supported by grants from Academia Sinica and Ministry of Science and Technology grants (MOST 104-0210-01-09-02, MOST 105-0210-01-13-01, MOST 106-0210-01-15-02, and MOST 108-2628-B-002-014). We like to thank Miss Tracy Tsai for her assists in immunohistochemistry works. And also like to thank the GRC Instrument Core Facilities for their support for the Affymetrix microarray, IVIS spectrum, and Aperio digital pathology analyses.

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  1. These authors contributed equally: Yung-Chieh Chan, Yu-Chan Chang, Hsiang-Hao Chuang

Authors and Affiliations

  1. Innovation Center, Show Chwan Memorial Hospital, Changhua, Taiwan

    Yung-Chieh Chan

  2. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Yu-Chan Chang & Michael Hsiao

  3. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Hsiang-Hao Chuang & Chih-Jen Yang

  4. Department of Medical Research, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

    Yi-Chieh Yang

  5. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yi-Chieh Yang & Yuan-Feng Lin

  6. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, E-DA Cancer Hospital, Kaohsiung, Taiwan

    Ming-Shyan Huang

  7. School of Medicine, I-Shou University, Kaohsiung, Taiwan

    Ming-Shyan Huang

  8. Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Michael Hsiao

  9. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chih-Jen Yang

  10. Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Kuo-Tai Hua

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Chan, YC., Chang, YC., Chuang, HH. et al. Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis. Oncogene 39, 2509–2522 (2020). https://doi.org/10.1038/s41388-020-1160-4

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