title: Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.
abstract: The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Lucía
authors: L
authors: Barbier-Torres
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Teresa C
authors: TC
authors: Delgado
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Juan L
authors: JL
authors: García-Rodríguez
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Imanol
authors: I
authors: Zubiete-Franco
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: David
authors: D
authors: Fernández-Ramos
authors: Department of Physiology, University of the Basque Country UPV/EHU, Faculty of Medicine and Dentistry, Leioa, Bizkaia, Spain.
authors: Xabier
authors: X
authors: Buqué
authors: OWL, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Ainara
authors: A
authors: Cano
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Virginia
authors: V
authors: Gutiérrez-de Juan
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Itziar
authors: I
authors: Fernández-Domínguez
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Fernando
authors: F
authors: Lopitz-Otsoa
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Pablo
authors: P
authors: Fernández-Tussy
authors: Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors: Loreto
authors: L
authors: Boix
authors: Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors: Jordi
authors: J
authors: Bruix
authors: Department of Gastroenterology, Azienda Ospedaliero-Universitaria & University of Modena and Reggio Emilia, Modena, Italy.
authors: Erica
authors: E
authors: Villa
authors: OWL, Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Azucena
authors: A
authors: Castro
authors: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, USA.
authors: Shelly C
authors: SC
authors: Lu
authors: Department of Physiology, University of the Basque Country UPV/EHU, Faculty of Medicine and Dentistry, Leioa, Bizkaia, Spain.
authors: Patricia
authors: P
authors: Aspichueta
authors: Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France.
authors: Dimitris
authors: D
authors: Xirodimas
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Marta
authors: M
authors: Varela-Rey
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: José M
authors: JM
authors: Mato
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: Naiara
authors: N
authors: Beraza
authors: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.
authors: María L
authors: ML
authors: Martínez-Chantar
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003517:Cyclopentanes / Q000494:pharmacology; D004734:Energy Metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D000075687:NEDD8 Protein; D000091402:Prohibitins; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C000717328:PHB protein, human; D000091402:Prohibitins; D011743:Pyrimidines; D012097:Repressor Proteins; D014452:Ubiquitins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C539933:pevonedistat
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