Neddylation, a novel paradigm in liver cancer

Abstract

Liver cancer is the sixth most prevailing cancer worldwide. Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, has a rather heterogeneous pathogenesis making it highly refractive to current therapeutic approaches. Hence, HCC patients have a poor and gloomy prognosis making liver cancer the second leading cause of global cancer-related deaths. On this basis, a more global mechanism, such as post-translational modifications (PTMs) of proteins, may provide a valuable therapeutic approach for HCC clinical management by simultaneously regulating multiple disrupted signaling pathways. In the last years, the ubiquitin-like molecule NEDD8 (Neural precursor cell-expressed developmentally downregulated-8) conjugation pathway, neddylation, was shown to be aberrant in HCC patients with a significant positive correlation found among global levels of neddylation and poorer prognosis. Even though the best-established role for NEDD8 is the activation of ubiquitin E3 ligase family of cullin-RING ligases, the putative role for other NEDD8 substrates has been explored in recent years leading to the identification of novel neddylation targets in HCC. Importantly, treatment with the small pharmacological inhibitor Pevonedistat (MLN4924) (Millennium Pharmaceuticals, Takeda Pharmaceutical), currently in clinical trials for the treatment of some types of leukemias and other advanced solid tumors, was shown to suppress the outgrowth of hepatoma cells and liver cancer in pre-clinical mouse models. Overall, considering that the neddylation inhibitor Pevonedistat was well-tolerated and displayed a significant antitumor effect in pre-clinical models, combinatory pharmacological treatment based on Pevonedistat are highly recommended to enter clinical trials targeting advanced HCC.

The NEDD8 cycle controlled by NEDP1 upon DNA damage is a regulatory module of the HSP70 ATPase activity

“…This finding defines a molecular basis for the reported defects in the NEDD8 cycle in tumors as evidenced by an increase in protein NEDDylation (Abidi and Xirodimas, 2015). Importantly, our findings on the role of NEDP1 in the DNA damage induced apoptosis through regulation of the HSP70-APAF1 module, provide potential mechanistic insights for the reported resistance of advanced HCC tumors to chemotherapy (Abidi and Xirodimas, 2015;Delgado et al, 2018). As inhibitors for the NEDD8 pathway are in Phase II clinical trials (Abidi 17 and Xirodimas, 2015), NEDP1 levels may provide a marker for the tumor response to these inhibitors.…”

“…GNMT is a tumor suppressor and deletion in mice results in the development of HCC (Martínez-Chantar et al, 2008). We chose this system as previous studies showed upregulation in protein NEDDylation in GNMT-/-derived HCC tumors (Delgado et al, 2018). We found that NEDP1 protein levels in liver tissue extracts are dramatically reduced in all tested HCC animals compared to control animals (Fig.…”

“…Defects in the NEDD8 cycle resulting in increased levels of NEDDylation have been reported in several types of cancers including lung adenocarcinomas, squamous-cell carcinoma and hepatocellular carcinoma and inhibitors of the NEDD8 pathway are in Phase II clinical trials (Abidi and Xirodimas, 2015;Barbier-Torres et al, 2015;Delgado et al, 2018). Protein NEDDylation is a reversible process.…”

Development of Nanobodies as first-in-class inhibitors for the NEDP1 deNEDDylating enzyme

“…The deNEDDylating enzyme NEDP1 is now established as a critical regulator of protein NEDDylation, implicated in the control of several cellular processes. Decrease in NEDP1 levels was recently proposed as a molecular basis for the observed increase in protein NEDDylation observed in hepatocellular carcinoma 19,21 . Therefore, the development of inhibitors for NEDP1 will provide important tools for studying the functions for this enzyme.…”

“…Recent studies indicated a role for NEDP1 in tumour progression; The upregulation of NEDD8 in hepatocellular carcinoma was related to a decrease in the levels of NEDP1. Importantly, decrease in NEDP1 levels provides resistance of tumour cells to DNA damage induced apoptosis 9, 19–21 .…”