LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression

Abstract

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2{Delta}13 splice variant also function as novel deacetylases that trigger metabolic reprogramming during malignant transformation. Integrated transcriptomic and metabolomic analysis revealed that L2{Delta}13-overexpressing transgenic mice displayed perturbed glucose and lipid metabolism, which was associated with increased hepatic fibrosis and enhanced formation of precancerous lesions induced by chemical carcinogens, such as carbon tetrachloride and N-nitrosomethylbenzylamine. Furthermore, both LOXL2 and L2{Delta}13 boosted glucose metabolism of esophageal tumor cells, thereby facilitating tumor cell proliferation in vitro and in vivo. Mechanistically, LOXL2 and L2{Delta}13 interacted physically with several glycolic proteins including aldolase A to enhance their enzymatic activities and mobilization from the actin cytoskeleton. Using SILAC followed by proteomic analysis, we identified LOXL2 as a deacetylase targeting metabolic proteins in esophageal cancer. Importantly, both LOXL2 and L2{Delta}13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2{Delta}13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2{Delta}13.