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

Ching-Hsien Chen, W. H. Chang, K. Y. Su, W. H. Ku, G. C. Chang, Q. S. Hong, Y. J. Hsiao, H. C. Chen, H. Y. Chen, Reen Wu, P. C. Yang, J. J.W. Chen, S. L. Yu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5674-5685
Number of pages12
JournalOncogene
Volume35
Issue number43
DOIs
StatePublished - Oct 27 2016

Fingerprint

Lung Neoplasms
Neoplasm Metastasis
Neoplasms
Molecular Models
Epithelial-Mesenchymal Transition
Protein Binding
Knockout Mice
Small Interfering RNA
Proteins
Down-Regulation
Phosphorylation
Amino Acids
Ectopic Gene Expression
In Vitro Techniques
Protein Domains
Inhibition (Psychology)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Chen, C-H., Chang, W. H., Su, K. Y., Ku, W. H., Chang, G. C., Hong, Q. S., ... Yu, S. L. (2016). HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms. Oncogene, 35(43), 5674-5685. https://doi.org/10.1038/onc.2016.106

HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms. / Chen, Ching-Hsien; Chang, W. H.; Su, K. Y.; Ku, W. H.; Chang, G. C.; Hong, Q. S.; Hsiao, Y. J.; Chen, H. C.; Chen, H. Y.; Wu, Reen; Yang, P. C.; Chen, J. J.W.; Yu, S. L.

In: Oncogene, Vol. 35, No. 43, 27.10.2016, p. 5674-5685.

Research output: Contribution to journalArticle

Chen, C-H, Chang, WH, Su, KY, Ku, WH, Chang, GC, Hong, QS, Hsiao, YJ, Chen, HC, Chen, HY, Wu, R, Yang, PC, Chen, JJW & Yu, SL 2016, 'HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms', Oncogene, vol. 35, no. 43, pp. 5674-5685. https://doi.org/10.1038/onc.2016.106
Chen, Ching-Hsien ; Chang, W. H. ; Su, K. Y. ; Ku, W. H. ; Chang, G. C. ; Hong, Q. S. ; Hsiao, Y. J. ; Chen, H. C. ; Chen, H. Y. ; Wu, Reen ; Yang, P. C. ; Chen, J. J.W. ; Yu, S. L. / HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms. In: Oncogene. 2016 ; Vol. 35, No. 43. pp. 5674-5685.
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