Abstract
Hepatocellular carcinoma (HCC), the most common liver cancer, is an important leading cause of death worldwide. Neddylation is a post-translational modification involved in several processes such as cell growth, viability and development. Importantly, the neddylation pathway is upregulated in liver cancer and specifically enriched in patients with poor prognosis. Hu antigen R (HuR), is a RNA-binding protein that stabilizes target mRNAs involved in hepatocyte proliferation, differentiation and malignant transformation. And notably, HuR levels are highly representative in liver and colon cancer. A ground-breaking knowledge about HCC has been to identify that neddylation plays a role in HCC by regulating the liver oncogenic driver HuR. In addition, the neddylation inhibitor MLN4924 has shown antitumoral effects in vitro and in vivo in liver cancer, partly through HuR destabilization. Importantly, high levels of HuR made hepatoma cells more resistant to neddylation inhibition while low levels of HuR sensitized cells to the treatment, suggesting that the levels of HuR determine the druggability of the neddylation pathway in HCC. Overall, our findings highlight the impact that neddylation plays in liver cancer and open a completely new area of research, paving the way for novel therapeutical approaches.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of death by malignancy [1]
In this work we have studied the role of Hu antigen R (HuR) in the mediation of the apoptotic response induced by neddylation inhibiton in liver cancer cells
We found that Neural precursor cell expressed (Nedd8) activating enzyme (NAE1) inhibition suppressed cancer cell growth in HepG2 and BCLC3 cells as demonstrated by the appearance of Poly ADP ribose polymerase (PARP) cleavage and an increase in caspase 3 activity (Fig. 1A-B)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of death by malignancy [1]. HuR ( known as ELAVL1) has been described to stabilize ARE-containing mRNAs [5, 6] and to modulate their translation, both enhancing and inhibiting it [7]. Many of the HuR-regulated mRNAs participate in the acquisition of cancer traits such as enhanced ability to proliferate, enhanced cell survival, elevation of local angiogenesis, evasion of immune recognition, and invasion and metastasis [9, 10]. HuR has been found elevated in the liver of cirrhotic patients, together with a prominent increase of the cytosolic localization [11]. HuR has been found highly expressed in the hepatocellular carcinoma (HCC)-derived SAMe-D cell line, in which it stabilizes HAUSP mRNA. HAUSP is an ubiquitin specific protease that stabilizes p53 in the cytosol inducing the cell cycle arrest and the apoptotic response [12]
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