Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer

Wang, Yufei; Zhao, Lina; Geng, Yi; Yuan, Hongfeng; Hou, Chunyu; Zhang, Huihui; Yang, Guang; Zhang, Xiaodong

doi:10.1038/s41401-022-00945-z

Cited by 15 publications

(14 citation statements)

References 40 publications

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“…As a potential inducer of ferroptosis, sulfasalazine enhanced the radiosensitivity in hypoxic colorectal cancer cells (Kerkhove et al, 2023). Aspirin, a traditional non‐steroidal antiinflammatory drug, is known to be effective in the prevention and treatment of cancer (Løfling et al, 2023; Y. F. Wang, Zhao, Geng, et al, 2023; Yun et al, 2022). Notably, aspirin could induce ferroptosis by modulating the nuclear factor κB (NF‐κB) p65/SLC7A11 axis and consequently inhibit the development of hepatocellular carcinoma (Y. F. Wang, Feng, Zhao, et al, 2023).…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Ferroptosis: Potential opportunities for natural products in cancer therapy

Nie,

Shen,

Zhou

et al. 2023

Phytotherapy Research

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Cancer cells often exhibit defects in the execution of cell death, resulting in poor clinical outcomes for patients with many cancer types. Ferroptosis is a newly discovered form of programmed cell death characterized by intracellular iron overload and lipid peroxidation in the cell membrane. Increasing evidence suggests that ferroptosis is closely associated with a wide variety of physiological and pathological processes, particularly in cancer. Notably, various bioactive natural products have been shown to induce the initiation and execution of ferroptosis in cancer cells, thereby exerting anticancer effects. In this review, we summarize the core regulatory mechanisms of ferroptosis and the multifaceted roles of ferroptosis in cancer. Importantly, we focus on natural products that regulate ferroptosis in cancer cells, such as terpenoids, polyphenols, alkaloids, steroids, quinones, and polysaccharides. The clinical efficacy, adverse effects, and drug–drug interactions of these natural products need to be evaluated in further high‐quality studies to accelerate their application in cancer treatment.

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Section: Conclusion and Future Perspectivementioning

confidence: 99%

Ferroptosis: Potential opportunities for natural products in cancer therapy

Nie,

Shen,

Zhou

et al. 2023

Phytotherapy Research

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“…As succinyl-CoA is a metabolite generated from the TCA cycle and succinylation is widely spread among diverse mitochondrial metabolic enzymes as well as extramitochondrial cytosolic and nuclear proteins, variations on the protein lysine succinylation level may be a reflection of different cell metabolic states ( 51 ). In general, chromatin succinylation is correlated with an active transcriptional program and promotive on aerobic glycolysis and cell proliferation, and the associations between succinylation and tumorigenesis have already been established in many studies ( 52 ) such as the tumor-promotive role of phosphoglycerate mutase 1 (PGAM1) K99 succinylation in liver cancers ( 53 ) and that of fibrillin 1 (FBN1) K672 succinylation in gastric cancers ( 54 ).…”

Section: Succinylation and Cancer Hallmarksmentioning

confidence: 99%

“…Succinylation can enhance the activity of target proteins. For instance, PGAM1, a key enzyme of glycolysis, accelerates carcinogenesis once hyper-activated; aspirin is capable of attenuating PGAM1 activity by removing its K99 succinylation in hepatoma cells that ultimately leads to halted tumor progression ( 53 ). Kidney-type GLS is highly represented in human pancreatic ductal adenocarcinoma specimens, the activity of which is enhanced after K311 succinylation, leading to increased glutaminolysis and elevated production of glutathione and NADPH to counteract oxidative stress for improved survival of transformed cells ( 58 ).…”

Section: Modes Of Succinylation Driving Cancer Hallmarksmentioning

confidence: 99%

Succinylation and redox status in cancer cells

et al. 2022

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Succinylation is a post-translational modification (PTM) event that associates metabolic reprogramming with various pathological disorders including cancers via transferring a succinyl group to a residue of the target protein in an enzymic or non-enzymic manner. With our incremental knowledge on the roles of PTM played in tumor initiation and progression, relatively little has been focused on succinylation and its clinical implications. By delineating the associations of succinylation with cancer hallmarks, we identify the, in general, promotive roles of succinylation in manifesting cancer hallmarks, and conceptualize two working modes of succinylation in driving oncogenic signaling, i.e., via altering the structure and charge of target proteins towards enhanced stability and activity. We also characterize succinylation as a reflection of cellular redox homeostatic status and metabolic state, and bring forth the possible use of hyper-succinylated genome for early cancer diagnosis or disease progression indication. In addition, we propose redox modulation tools such as cold atmospheric plasma as a promising intervention approach against tumor cells and cancer stemness via targeting the redox homeostatic environment cells established under a pathological condition such as hypoxia. Taken together, we emphasize the central role of succinylation in bridging the gap between cellular metabolism and redox status, and its clinical relevance as a mark for cancer diagnosis as well as a target in onco-therapeutics.

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“…Zhou et al [ 21 ] confirmed that KAT2A promotes the succinylation of K46 and K280 of C-terminal binding protein 1 and mediates the transcription-suppressing activity. In addition, histone acetyltransferase 1 (HAT1) was identified as a succinyltransferase of both histone and non-histone proteins[ 17 , 22 ]. HAT1 mediates the succinylation of histones, and quantitative proteomic analysis revealed five succinylation sites on 45 histones[ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Wang et al [ 22 ] and Yang et al [ 17 ] demonstrated that phosphoglycerate mutase 1 (PGAM1), a critical enzyme in glycolysis, is succinylated by HAT1 at K99. The later report also mentioned that aspirin downregulates HAT1 by targeting NF-kappaB to induce PGAM1 K99 desuccinylation, which suppresses the glycolytic process[ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Protein succinylation, hepatic metabolism, and liver diseases

Liu,

Li,

Sun

et al. 2024

World J Hepatol

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Succinylation is a highly conserved post-translational modiﬁcation that is processed via enzymatic and non-enzymatic mechanisms. Succinylation exhibits strong effects on protein stability, enzyme activity, and transcriptional regulation. Protein succinylation is extensively present in the liver, and increasing evidence has demonstrated that succinylation is closely related to hepatic metabolism. For instance, histone acetyltransferase 1 promotes liver glycolysis, and the sirtuin 5-induced desuccinylation is involved in the regulation of the hepatic urea cycle and lipid metabolism. Therefore, the effects of succinylation on hepatic glucose, amino acid, and lipid metabolism under the action of various enzymes will be discussed in this work. In addition, how succinylases regulate the progression of different liver diseases will be reviewed, including the desuccinylation activity of sirtuin 7, which is closely associated with fatty liver disease and hepatitis, and the actions of lysine acetyltransferase 2A and histone acetyltransferase 1 that act as succinyltransferases to regulate the succinylation of target genes that influence the development of hepatocellular carcinoma. In view of the diversity and significance of protein succinylation, targeting the succinylation pathway may serve as an attractive direction for the treatment of liver diseases.

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Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer

Cited by 15 publications

References 40 publications

Ferroptosis: Potential opportunities for natural products in cancer therapy

Ferroptosis: Potential opportunities for natural products in cancer therapy

Succinylation and redox status in cancer cells

Protein succinylation, hepatic metabolism, and liver diseases

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