Lysyl Hydroxylase 2 Glucosylates Collagen VI To Drive Lung Cancer Progression

Authors

Shike Wang
Houfu Guo
Reo Fukushima
Masahiko Terajima
Min Liu
Guan-Yu Xiao
Lenka Koudelková
Chao Wu
Xin Liu
Jiang Yu
Emma Burris
Jun Xu
Alvise Schiavinato
William K Russell
Mitsuo Yamauchi
Xiaochao Tan
Jonathan M Kurie

Publication Date

4-1-2025

Journal

Journal of Clinical Investigation

Abstract

Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. 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 α3 (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's GGT domain in cancer cells.

Keywords

Humans, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Lung Neoplasms, Animals, Glycosylation, Mice, Collagen Type VI, Adenocarcinoma of Lung, Disease Progression, Cell Line, Tumor, Neoplasm Proteins, Protein Domains, Adenocarcinoma, Cell Movement, Cell biology, Oncology, Collagens, Integrins, Lung cancer

DOI

10.1172/JCI189197

PMID

40166934

PMCID

PMC11957695

PubMedCentral® Posted Date

4-1-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes