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

Ji-Wei Jiao; Xiu-Hui Zhan; Juan-Juan Wang; Li-Xia He; Zhen-Chang Guo; Xiu-E Xu; Lian-Di Liao; Xin Huang; Bing Wen; Yi-Wei Xu; Hai Hu; Gera Neufeld; Zhi-Jie Chang; Kai Zhang; Li-Yan Xu; En-Min Li

doi:10.1016/j.redox.2022.102496

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

Redox Biol. 2022 Nov:57:102496. doi: 10.1016/j.redox.2022.102496. Epub 2022 Oct 3.

Authors

Ji-Wei Jiao¹, Xiu-Hui Zhan², Juan-Juan Wang³, Li-Xia He³, Zhen-Chang Guo⁴, Xiu-E Xu³, Lian-Di Liao¹, Xin Huang⁵, Bing Wen¹, Yi-Wei Xu⁶, Hai Hu⁷, Gera Neufeld⁸, Zhi-Jie Chang⁹, Kai Zhang¹⁰, Li-Yan Xu¹¹, En-Min Li¹²

Affiliations

¹ The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, China.
² Department of Orthopedics, Research Center of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
³ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, China.
⁴ The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, China; Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, 300070, China.
⁵ Department of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
⁶ Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China.
⁷ Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
⁸ Technion Integrated Cancer Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 31096, Israel.
⁹ State Key Laboratory of Membrane Biology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, 10084, China.
¹⁰ Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, 300070, China. Electronic address: kzhang@tmu.edu.cn.
¹¹ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, China. Electronic address: lyxu@stu.edu.cn.
¹² The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, China. Electronic address: nmli@stu.edu.cn.

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 L2Δ13 splice variant boost glucose metabolism of esophageal tumor cells, facilitate tumor cell proliferation and promote tumor development in vivo. Consistently, integrated transcriptomic and metabolomic analysis of a knock-in mouse model expressing L2Δ13 gene revealed that LOXL2/L2Δ13 overexpression perturbs glucose and lipid metabolism. Mechanistically, we identified aldolase A, glyceraldehyde-3-phosphate dehydrogenase and enolase as glycolytic proteins that interact physically with LOXL2 and L2Δ13. In the case of aldolase A, LOXL2/L2Δ13 stimulated its mobilization from the actin cytoskeleton to enhance aldolase activity during malignant transformation. Using stable isotope labeling of amino acids in cell culture (SILAC) followed by proteomic analysis, we identified LOXL2 and L2Δ13 as novel deacetylases that trigger metabolic reprogramming. Both LOXL2 and L2Δ13 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/L2Δ13 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 L2Δ13. HIGHLIGHT OF THE STUDY: LOXL2 and its catalytically inactive isoform L2Δ13 function as new deacetylases to promote metabolic reprogramming and tumor progression in esophageal cancer by directly activating glycolytic enzymes such as aldolase A.

Keywords: Aldolase; Deacetylation; Glycolysis; Lysyl oxidase-like 2; Tumorigenesis.