Lysyl hydroxylase 2 is secreted by tumor cells and can modify collagen in the extracellular space

Yulong Chen, Houfu Guo, Masahiko Terajima, Priyam Banerjee, Xin Liu, Jiang Yu, Amin A. Momin, Hiroyuki Katayama, Samir M. Hanash, Alan R. Burns, Gregg B. Fields, Mitsuo Yamauchi, Jonathan M. Kurie

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Lysyl hydroxylase 2 (LH2) catalyzes the hydroxylation of lysine residues in the telopeptides of fibrillar collagens, which leads to the formation of stable collagen cross-links. Recently we reported that LH2 enhances the metastatic propensity of lung cancer by increasing the amount of stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), which generate a stiffer tumor stroma (Chen, Y., et al. (2015) J. Clin. Invest. 125, 125, 1147-1162). It is generally accepted that LH2 modifies procollagen α chains on the endoplasmic reticulum before the formation of triple helical procollagen molecules. Herein, we report that LH2 is also secreted and modifies collagen in the extracellular space. Analyses of lung cancer cell lines demonstrated that LH2 is present in the cell lysates and the conditioned media in a dimeric, active form in both compartments. LH2 colocalized with collagen fibrils in the extracellular space in human lung cancer specimens and in orthotopic lung tumors generated by injection of a LH2-expressing human lung cancer cell line into nude mice. LH2 depletion in MC3T3 osteoblastic cells impaired the formation of HLCCs, resulting in an increase in the unmodified lysine aldehyde-derived collagen cross-link (LCC), and the addition of recombinant LH2 to the media of LH2-deficient MC3T3 cells was sufficient to rescue HLCC formation in the extracellular matrix. The finding that LH2 modifies collagen in the extracellular space challenges the current view that LH2 functions solely on the endoplasmic reticulum and could also have important implications for cancer biology.

Original languageEnglish
Pages (from-to)25799-25808
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number50
DOIs
StatePublished - Dec 9 2016

Bibliographical note

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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