title: MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation.
abstract: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer death in the world. Fructose-1,6-biphosphatase (FBP1), a rate-limiting enzyme in gluconeogenesis, has been identified recently as a tumor suppressor in HCC and other cancer types. In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. We further showed that expression of TRIM28 increased glucose consumption and lactate production by promoting FBP1 degradation in HCC cells and that FBP1 is a key mediator of TRIM28-induced HCC growth in culture and in mice. Moreover, we demonstrated that FBP1 and TRIM28 protein levels inversely correlated in HCC patient specimens. Finally, we showed that the proteasome inhibitor bortezomib mitigated the Warburg effect by inhibiting FBP1 degradation in HCC. Collectively, our findings not only identify oncogenic MAGE-TRIM28 complex-mediated proteasome degradation of FBP1 as a key mechanism underlying downregulation of FBP1 proteins in HCC, but also reveal that MAGE-TRIM28-regulated reprogramming of cancer cell metabolism and HCC tumorigenesis is mediated, at least in part, through FBP1 degradation.
authors.affiliation: Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Medical Informatics and Statistics, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: L
authors.identifier: http://orcid.org/0000-0003-2072-4826
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ravichandran
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Potts
authors.affiliation: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang