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2017 ; 6
(4
): e312
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MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma
progression by targeting FBP1 for degradation
#MMPMID28394358
Jin X
; Pan Y
; Wang L
; Zhang L
; Ravichandran R
; Potts PR
; Jiang J
; Wu H
; Huang H
Oncogenesis
2017[Apr]; 6
(4
): e312
PMID28394358
show ga
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.