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HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms

Oncogene volume 35, pages 5674–5685 (2016)Cite this article

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Abstract

HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial–mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1–Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1–Src complex might provide a promising molecular model for developing new anticancer strategies.

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Acknowledgements

We thank Dr Po-Chao Chan (Department of Life Science, National Chung Hsing University, Taichung, Taiwan) and Dr Samuel Chung (Department of Internal Medicine, University of California Davis, Davis, CA, USA) for useful discussion; Dr Yung-Hao Wong (Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan) for the advice regarding protein docking; Dr Yu-Ching Lin (UNIMED Healthcare Inc., Taiwan) and the Center for Innovative Therapeutics Discovery of National Taiwan University for technological support in ForteBio system; and the Integrated Core Facility for Functional Genomics of the National Core Facility Program for Biotechnology (NCFPB) for technological support. This work was supported by grants from the Ministry of Science and Technology, Taiwan, ROC (NSC 98-2314-B-005-001-MY3, NSC 102-2911-I-002-303 and NSC 103-2911-I-002-303) and National Taiwan University (102R7557 and 103R7557), as well as in part by the Tobacco-Related Disease Research Program (TRDRP; 23FT-0104 to C-H Chen) and by the Ministry of Education, Taiwan, ROC under the ATU plan.

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Author notes

  1. C-H Chen, W-H Chang, J J W Chen and S-L Yu: These authors co-directed the project and contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, CA, USA

    C-H Chen & R Wu

  2. Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA

    C-H Chen

  3. Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    W-H Chang & P-C Yang

  4. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan

    K-Y Su, Q-S Hong, Y-J Hsiao & S-L Yu

  5. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    K-Y Su & S-L Yu

  6. Taipei Institute of Pathology, Taipei, Taiwan

    W-H Ku

  7. Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    G-C Chang

  8. Department of Life Science, National Chung Hsing University, Taichung, Taiwan

    H-C Chen

  9. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

    H-Y Chen

  10. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    P-C Yang

  11. Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

    J J W Chen

  12. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

    J J W Chen

  13. Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan

    S-L Yu

  14. Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    S-L Yu

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Correspondence to J J W Chen or S-L Yu.

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Chen, CH., Chang, WH., Su, KY. et al. HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms. Oncogene 35, 5674–5685 (2016). https://doi.org/10.1038/onc.2016.106

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