A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma

Feng, Yuhua; Zhang, Ye; Cai, Yi; Liu, Ruijie; Lu, Min-qiang; Li, Tangzhiming; Fu, Ying; Guo, Ming; Huang, Huichao; Ou, Yifu; Chen, Yongheng

doi:10.1038/s41419-020-2278-6

Cited by 67 publications

(59 citation statements)

References 39 publications

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“…Apart from this, we proved that A20 played a crucial role in glycolysis, with the expressions of a series of glycolytic enzymes significantly decreased after the knockdown of A20. This finding was in contrary to two previous reports demonstrating that A20 exerted negative impact on glycolysis in hepatocellular carcinoma and leukemia 44,46 . The discrepancy may be due to the heterogeneity of distinct tumor types, which indicated that tumor context should be taken into consideration for A20-based metabolism intervention in cancer therapy.…”

Section: Discussioncontrasting

confidence: 99%

A20 promotes melanoma progression via the activation of Akt pathway

Wang

Guo

et al. 2020

Cell Death Dis

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Melanoma is the most life-threatening skin cancer with increasing incidence around the world. Although recent advances in targeted therapy and immunotherapy have brought revolutionary progress of the treatment outcome, the survival of patients with advanced melanoma remains unoptimistic, and metastatic melanoma is still an incurable disease. Therefore, to further understand the mechanism underlying melanoma pathogenesis could be helpful for developing novel therapeutic strategy. A20 is a crucial ubiquitin-editing enzyme implicated immunity regulation, inflammatory responses and cancer pathogenesis. Herein, we report that A20 played an oncogenic role in melanoma. We first found that the expression of A20 was significantly up-regulated in melanoma cell lines. Then, we showed that knockdown of A20 suppressed melanoma cell proliferation in vitro and melanoma growth in vivo through the regulation of cell-cycle progression. Moreover, A20 could potentiate the invasive and migratory capacities of melanoma cell in vitro and melanoma metastasis in vivo by promoting epithelial–mesenchymal transition (EMT). Mechanistically, we found that Akt activation mediated the oncogenic effect of A20 on melanoma development, with the involvement of glycolysis. What’s more, the up-regulation of A20 conferred the acquired resistance to Vemurafenib in BRAF-mutant melanoma. Taken together, we demonstrated that up-regulated A20 promoted melanoma progression via the activation of Akt pathway, and that A20 could be exploited as a potential therapeutic target for melanoma treatment.

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Section: Discussioncontrasting

confidence: 99%

A20 promotes melanoma progression via the activation of Akt pathway

Wang

Guo

et al. 2020

Cell Death Dis

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“…Phosphofructokinase (PFK), the second rate-limiting enzyme in glycolysis, is a key regulator of glycolytic flux in cancer cells. Decreased A20 mediated ubiquitination and degradation of PFK liver type (PFKL) are related to increased glycolysis during hepatocellular carcinoma progression [254]. Phosphorylation of PFK1 platelet isoform (PFKP) by AKT can prevent it from TRIM21mediated ubiquitination and degradation, promoting aerobic glycolysis in glioblastoma cells [255].…”

Section: Ubiquitination and Metabolic Enzymesmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

260

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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“…The A20-KO in hepatocytes results in chronic liver inflammation, as well as increased inflammation induction by pro-inflammatory stimulants like LPS or TNF, as well as enhanced susceptibility to HCC [ 125 ]. The protective properties of A20 towards HCC progression have been shown in another study, where A20 acts as an E3 Ub-ligase for a liver-type phosphofructokinase (PFKL) [ 133 ]. This leads to the inhibition of glycolysis and ceases cancerous proliferation, hence the evidence for the potential antitumor role of A20 emerges [ 133 ].…”

Section: Nf-κb-regulating Molecular Factorsmentioning

confidence: 99%

The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

Nowak

Relja

2020

IJMS

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Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

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A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma

Cited by 67 publications

References 39 publications

A20 promotes melanoma progression via the activation of Akt pathway

A20 promotes melanoma progression via the activation of Akt pathway

The role of ubiquitination and deubiquitination in cancer metabolism

The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

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