Abstract
Abnormal expression of the E3 ubiquitin ligase A20 has been found in some malignant cancers, including hepatocellular carcinoma (HCC). Here, we discovered that A20 is an E3 ubiquitin ligase for phosphofructokinase, liver type (PFKL) in HCC A20 interacts with PFKL and promotes its degradation, therefore inhibiting glycolysis in HCC cell lines. Downregulation of A20 in HCC cells promotes proliferation, migration, and glycolysis, all of which can be inhibited by targeting PFKL with RNA interference. Importantly, A20 is downregulated in advanced HCC tissues and inversely correlated with PFKL expression. Thus, our findings establish A20 as a critical regulator of glycolysis and reveal a novel mechanism for A20 in tumor suppression and PFKL regulation. Given that an increased level of glycolysis is linked with HCC, this study also identifies potential therapeutic targets for HCC treatment.
Highlights
Ubiquitination-proteasome mediated degradation is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis
A20 knockdown enhanced cell proliferation, clone formation, and migration, while A20 overexpression suppressed these capacities in hepatocellular carcinoma (HCC) cells, both in vitro and in vivo (Fig. 1a–d and Supplementary Fig. S1b)
Huh[7] cells devoid of A20 displayed substantially increased glycolytic capacity, whereas overexpressing A20 cells showed substantially reduced glycolytic capacity (Fig. 1g, h). These findings demonstrate that A20 plays a negative role in HCC proliferation, migration, and glucose metabolism
Summary
Ubiquitination-proteasome mediated degradation is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis This process is carried out by three enzymes ubiquitin activating enzyme (E1), ubiquitin-conjugase (E2), and ubiquitin ligase (E3), in which the E3 ubiquitin ligases are responsible for targeting specific substrates (proteins) for ubiquitin-mediated degradation[1,2]. In cancer cells, the stability and the balance between oncoproteins and tumor suppressor proteins are disturbed in part due to deregulated E3 ubiquitin ligases. This leads to either stabilization of oncoprotein(s) or increased degradation of tumor suppressor(s), contributing to tumorigenesis and cancer progression. The Official journal of the Cell Death Differentiation Association
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