Lysyl Hydroxylase 2 Is Secreted by Tumor Cells and Can Modify Collagen in the Extracellular Space.
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.
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Yulong
Y
Chen
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Houfu
H
Guo
Oral and Craniofacial Health Sciences, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
Masahiko
M
Terajima
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Priyam
P
Banerjee
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Xin
X
Liu
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Jiang
J
Yu
the Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Amin A
AA
Momin
the Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Hiroyuki
H
Katayama
the Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Samir M
SM
Hanash
the College of Optometry, University of Houston, Houston, Texas 77004, and.
Alan R
AR
Burns
the Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, Florida 33458.
Gregg B
GB
Fields
Oral and Craniofacial Health Sciences, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, mitsuo_yamauchi@unc.edu.
Mitsuo
M
Yamauchi
From the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, jkurie@mdanderson.org.
Jonathan M
JM
Kurie
D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
D009363:Neoplasm Proteins; D003094:Collagen; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C582419:lysyl hydroxylase 2, mouse
collagen; extracellular matrix; hydroxylysine (Hyl); lysine; lysyl hydroxylase 2; post-translational modification (PTM); secretion