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.

Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction

“…1A; Supplementary Table S2; ref. 16). Given that IQGAP1 is a scaffold protein that plays an important role in activation of the RAF–MEK–ERK pathway and tumorigenesis in PDAC (8, 17), we were interested in exploring the molecular basis and biological impact of the interaction between FBP1 and IQGAP1 in PDAC.…”

Regulation of MAGE ‐A3/6 by the CRL 4‐ DCAF 12 ubiquitin ligase and nutrient availability

“…Importantly, MAGE-A3/6 drives cellular transformation, tumor growth, and metastasis [10,16,18]. Specifically, MAGE-A3/6 drives ubiquitination and degradation of two key metabolic enzymes and tumor suppressors, 5 0 adenosine monophosphate-activated protein kinase (AMPK) and fructose-1,6-bisphosphatase 1 (FBP1), by the TRIM28 E3 ubiquitin ligase [10,[19][20][21][22]. Specifically, MAGE-A3/6 drives ubiquitination and degradation of two key metabolic enzymes and tumor suppressors, 5 0 adenosine monophosphate-activated protein kinase (AMPK) and fructose-1,6-bisphosphatase 1 (FBP1), by the TRIM28 E3 ubiquitin ligase [10,[19][20][21][22].…”

“…Specifically, MAGE-A3/6 drives ubiquitination and degradation of two key metabolic enzymes and tumor suppressors, 5 0 adenosine monophosphate-activated protein kinase (AMPK) and fructose-1,6-bisphosphatase 1 (FBP1), by the TRIM28 E3 ubiquitin ligase [10,[19][20][21][22]. Thus, MAGE-A3/6 promotes glycolysis and the Warburg effect through degradation of FBP1 [19]. This reaction is a rate-limiting step in gluconeogenesis and inhibits glycolysis and the Warburg effect [23].…”

“…This reaction is a rate-limiting step in gluconeogenesis and inhibits glycolysis and the Warburg effect [23]. Thus, MAGE-A3/6 promotes glycolysis and the Warburg effect through degradation of FBP1 [19]. AMPK is another key energy homeostasis enzyme that controls a plethora of cellular pathways [24].…”

Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

“…We observed that Tat expression was inversely proportional to KAP1 expression level suggesting that KAP1-mediated repression of Tat function results from Tat degradation. KAP1 has been shown to promote proteasomal degradation of targets proteins by its RBCC domain (53)(54)(55). Surprisingly, we observed that Tat degradation was not sensitive to RBCC depletion but mediated by the PHD and the Bromo domains of KAP1.…”