Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space.

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 co-localized 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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 50 Pg. 25799-25808 (Dec 09 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27803159 (Publication Type: Journal Article)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Neoplasm Proteins
• Collagen
• PLOD2 protein, human
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
• lysyl hydroxylase 2, mouse

Topics

• Animals
• Cell Line, Tumor
• Collagen (genetics, metabolism)
• Extracellular Matrix (genetics, metabolism)
• Humans
• Mice
• Neoplasm Proteins (genetics, metabolism)
• Neoplasms (genetics, metabolism)
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (genetics, metabolism)
• Protein Processing, Post-Translational