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.

Deregulated neddylation in liver fibrosis

“…This is in agreement with earlier evidence where increased death as a result of necrosis was observed in BDL, whereas high toxic BA was shown to induce apoptosis in cultured hepatocytes . Of note, neddylation inhibition either by MLN4924‐treatment or Nae1 silencing significantly reduced caspase 3 activity only in DCA‐stimulated hepatocytes not inducing apoptosis per se , indicating that neddylation inhibition‐mediated cell death is exclusively of dividing hepatoma cells or pretumoural hepatocytes, as observed . Overall, these data suggest that neddylation could mediate hepatocyte death in liver injury.…”

“…Previously, other investigators have shown that Cullin 7, a well‐described Nedd8 substrate, is a novel gene potentially involved in liver carcinogenesis, an end stage of LF. Moreover, our group has recently shown that neddylation activity is aberrant in HCC . Herein, we provide strong evidence that neddylation is up‐regulated in clinical LF from different etiologies as well as in two distinct animal models that mimic the progression of fibrosis observed in patients, the BDL‐ and the CCl 4 ‐induced liver injury.…”

“…In recent years, several reports of noncullin neddylation targets indicate that Nedd8 might have additional biological functions . In the liver context, several neddylation targets were found to be disrupted in liver tumors from HCC patients . In spite of this, the relevance of neddylation modifications in LF, especially focusing on HSCs, the major fibrogenic cell type and highly refractive to current therapies, remained rather unexplored.…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Mechanistically, the LKB1 inactivation induced tumorigenesis is mainly attributed to metabolic reprogramming towards a more anabolic phenotype following the failure of the LKB1-AMPK pathway [47], Moreover, LKB1 silencing contributes to the redox imbalance and resultant chemoresistance in non-small cell lung carcinoma [48]. The CCL2-mediated macrophage recruitment is enhanced in part due to the loss-of-function mutation on LKB1 , which partially explains the development of endometrial cancer [49].…”

The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity

“…Studies on non-cullin NEDD8 substrates identified additional roles of protein NEDDylation, including transcriptional activity and tumour suppressor function regulation, signalling, cell metabolism, apoptosis and histone modification12. Furthermore, global NEDDylation and expression of components of the NEDD8 machinery such as NAE and Ubc12 are found upregulated in lung adenocarcinoma, squamous-cell carcinomas and hepatocellular carcinoma456. Therefore, the NEDD8 pathway is implicated in the control of multiple cancer-related biological processes.…”