Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression

Authors

Shike Wang, The University of Texas MD Anderson Cancer CenterFollow
Houfu Guo, University of Kentucky
Reo Fukushima, University of North Carolina at Chapel Hill
Masahiko Terajima, University of North Carolina at Chapel Hill
Min Liu, The University of Texas MD Anderson Cancer Center
Guan-Yu Xiao, University of KentuckyFollow
Lenka Koudelková, The University of Texas MD Anderson Cancer Center
Chao Wu, The University of Texas MD Anderson Cancer Center
Xin Liu, The University of Texas MD Anderson Cancer Center
Jiang Yu, The University of Texas MD Anderson Cancer Center
Emma Burris, University of St Thomas
Jun Xu, Baylor College of Medicine
Alvise Schiavinato, University of Cologne
William K. Russell, The University of Texas Medical Branch
Mitsuo Yamauchi, University of North Carolina at Chapel Hill
Xiaochao Tan, Tulane UniversityFollow

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.

Document Type

Article

Publication Date

4-2025

Notes/Citation Information

Copyright © 2025 American Society for Clinical Investigation

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI189197

Funding Information

This work was supported in part by the NIH (1R01CA251067 and Lung SPORE P50CA070907) (JMK). JMK holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. WKR acknowledges support from the Cancer Prevention Research Institute of Texas (Grant: RP190682).

Repository Citation

Wang, Shike; Guo, Houfu; Fukushima, Reo; Terajima, Masahiko; Liu, Min; Xiao, Guan-Yu; Koudelková, Lenka; Wu, Chao; Liu, Xin; Yu, Jiang; Burris, Emma; Xu, Jun; Schiavinato, Alvise; Russell, William K.; Yamauchi, Mitsuo; and Tan, Xiaochao, "Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression" (2025). Markey Cancer Center Faculty Publications. 425.
https://uknowledge.uky.edu/markey_facpub/425