MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation

X. Jin, Y. Pan, Liguo Wang, Lizhi Zhang, R. Ravichandran, P. R. Potts, J. Jiang, H. Wu, Haojie Huang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere312
JournalOncogenesis
Volume6
Issue number4
DOIs
StatePublished - Jan 1 2017

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Hepatocellular Carcinoma
Neoplasms
Fructose-Bisphosphatase
Tripartite Motif Proteins
Proteasome Inhibitors
Gluconeogenesis
Ubiquitination
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Cause of Death
Lactic Acid
Carcinogenesis
Proteins
Down-Regulation
Glucose
Enzymes
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation. / Jin, X.; Pan, Y.; Wang, Liguo; Zhang, Lizhi; Ravichandran, R.; Potts, P. R.; Jiang, J.; Wu, H.; Huang, Haojie.

In: Oncogenesis, Vol. 6, No. 4, e312, 01.01.2017.

Research output: Contribution to journalArticle

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