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Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2 modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain \u03b13 (Col6a3), a component of the Col6 heterotrimeric molecule, as a candidate LH2 substrate. In gain- and loss-of-function studies, high Col6a3 levels increased tumor growth and metastatic activity and enhanced the proliferative, migratory, and invasive activities of LUAD cells. LH2 coimmunoprecipitated with Col6a3, and LH2 glucosylated Col6 in an in vitro reaction. Glucosylation increased the integrin-binding and promigratory activities of Col6 in LUAD cells. Col6a3 K2049 was deglucosylated in GGT-inactive tumor samples, and mutagenesis of Col6a3 K2049 phenocopied Col6a3 deficiency or LH2 GGT domain inactivation in LUAD cells. Thus, LH2 glucosylates Col6 to drive LUAD progression. These findings show that the GGT domain of LH2 is protumorigenic, identify Col6 as a candidate effector, and provide a rationale to develop pharmacological strategies that target LH2\u2019s GGT domain in cancer cells.<\/jats:p>","DOI":"10.1172\/jci189197","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T14:01:19Z","timestamp":1743429679000},"source":"Crossref","is-referenced-by-count":4,"title":["Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression"],"prefix":"10.1172","volume":"135","author":[{"given":"Shike","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Thoracic\/Head and Neck Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houfu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reo","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Terajima","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3454-6717","authenticated-orcid":true,"given":"Guan-Yu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Koudelkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Thoracic\/Head and Neck Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Thoracic\/Head and Neck Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thoracic\/Head and Neck Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Thoracic\/Head and Neck Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Burris","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology, University of St Thomas, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, The Advanced Cell Engineering and 3D Models Core, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvise","family":"Schiavinato","sequence":"additional","affiliation":[{"name":"Center for Biochemistry, University of Cologne, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1931-4555","authenticated-orcid":true,"given":"William K.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8603-5700","authenticated-orcid":true,"given":"Xiaochao","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Tulane School of Medicine. 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