LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression
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 inact...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722002683 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ji-Wei Jiao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T17:58:22Z |
| format | Article |
| id | doaj.art-4845795eb09b42b2917759efefea0337 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T17:58:22Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
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| series | Redox Biology |
| spelling | doaj.art-4845795eb09b42b2917759efefea03372022-12-22T03:22:15ZengElsevierRedox Biology2213-23172022-11-0157102496LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progressionJi-Wei Jiao0Xiu-Hui Zhan1Juan-Juan Wang2Li-Xia He3Zhen-Chang Guo4Xiu-E Xu5Lian-Di Liao6Xin Huang7Bing Wen8Yi-Wei Xu9Hai Hu10Gera Neufeld11Zhi-Jie Chang12Kai Zhang13Li-Yan Xu14En-Min Li15The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, ChinaDepartment of Orthopedics, Research Center of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, ChinaGuangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, ChinaGuangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, ChinaThe 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, ChinaGuangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, ChinaThe Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, ChinaDepartment of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, ChinaThe Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, ChinaDepartment of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, 515041, ChinaDepartment of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, ChinaTechnion Integrated Cancer Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 31096, IsraelState Key Laboratory of Membrane Biology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, 10084, ChinaDepartment of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, 300070, China; Corresponding author. Tianjin Medical University, No.22, Qixiangtai Road, Tianjin, 300070, China.Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, China; Corresponding author. Shantou University Medical College, No. 22, Xinling Road, Shantou, 515041, Guangdong, China.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; Corresponding author. Shantou University Medical College, No. 22, Xinling Road, Shantou, 515041, Guangdong, China.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.http://www.sciencedirect.com/science/article/pii/S2213231722002683Lysyl oxidase-like 2AldolaseGlycolysisDeacetylationTumorigenesis |
| spellingShingle | 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 LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression Redox Biology Lysyl oxidase-like 2 Aldolase Glycolysis Deacetylation Tumorigenesis |
| title | LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression |
| title_full | LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression |
| title_fullStr | LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression |
| title_full_unstemmed | LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression |
| title_short | LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression |
| title_sort | loxl2 dependent deacetylation of aldolase a induces metabolic reprogramming and tumor progression |
| topic | Lysyl oxidase-like 2 Aldolase Glycolysis Deacetylation Tumorigenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722002683 |
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