A collagen glucosyltransferase drives lung adenocarcinoma progression in mice.

Abstract

Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen's amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Here, we show that electrostatic interactions between the LH domain active site and collagen determine the unique telopeptidyl lysyl hydroxylase (tLH) activity of LH2. However, CRISPR/Cas-9-mediated inactivation of tLH activity does not fully recapitulate the inhibitory effect of LH2 knock out on LUAD growth and metastasis in mice, suggesting that LH2 drives LUAD progression, in part, through a tLH-independent mechanism. Protein homology modeling and biochemical studies identify an LH2 isoform (LH2b) that has previously undetected collagen galactosylhydroxylysyl glucosyltransferase (GGT) activity determined by a loop that enhances UDP-glucose-binding in the GLT active site and is encoded by alternatively spliced exon 13 A. CRISPR/Cas-9-mediated deletion of exon 13 A sharply reduces the growth and metastasis of LH2b-expressing LUADs in mice. These findings identify a previously unrecognized collagen GGT activity that drives LUAD progression.

• Authors: Hou-Fu Guo, Neus Bota-Rabassedas, Masahiko Terajima, B Leticia Rodriguez, Don L Gibbons, Yulong Chen, Priyam Banerjee, Chi-Lin Tsai, Xiaochao Tan, Xin Liu, Jiang Yu, Michal Tokmina-Roszyk, Roma Stawikowska, Gregg B Fields, Mitchell D Miller, Xiaoyan Wang, Juhoon Lee, Kevin N Dalby, Chad J Creighton, George N Phillips Jr, John A Tainer, Mitsuo Yamauchi, Jonathan M Kurie
• Journal: Communications biology (Commun Biol) Vol. 4 Issue 1 Pg. 482 (04 19 2021) ISSN: 2399-3642 [Electronic] England
• PMID: 33875777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucosyltransferases
• UDP glucose-collagen glucosyltransferase

Topics

• Adenocarcinoma of Lung (physiopathology)
• Animals
• Disease Progression
• Glucosyltransferases (metabolism)
• Lung Neoplasms (physiopathology)
• Mice