DNA Methylation of Cannabinoid Receptor Interacting Protein 1 Promotes Pathogenesis of Intrahepatic Cholangiocarcinoma Through Suppressing Parkin‐Dependent Pyruvate Kinase M2 Ubiquitination

Chen, Diyu; Wu, Hao; Feng, Xiaode; Chen, Yunhao; Lv, Zhen; Kota, Vishnu Goutham; Chen, Junru; Wu, Wenxuan; Lu, Yuejie; Liu, Hua; Zhang, Yanpeng; Zheng, Shusen; Wu, Jian

doi:10.1002/hep.31561

Cited by 18 publications

(13 citation statements)

References 46 publications

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“…USP20 can deubiquitinate PKM2 without affecting PKM2 expression [36]. Chen et al reported that Parkin modulated protein degradation of PKM2, while Liu et al found that Parkin ubiquitylated PKM2 at K186 and K206 to inhibit enzymatic activity of PKM2 without affecting PKM2 stability [34,37]. Viana et al [39] observed that laforin/malin E3 ligase complex catalyzes K63-linked ubiquitination of PKM2, which interferes with the localization of PKM2 to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitination is another common and essential type of post‐translational modification; however, its functions in the regulation of PKM2 oligomers are still poorly known. PKM2 was reported to interact with E3 ligases including Parkin, CHIP, TRIM58, and laforin/malin complex, as well as DUBs including HAUSP and USP20 [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. CHIP and HAUSP participate in the regulation of ubiquitination and stability of PKM2 protein [ 35 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…reported that Parkin modulated protein degradation of PKM2, while Liu et al . found that Parkin ubiquitylated PKM2 at K186 and K206 to inhibit enzymatic activity of PKM2 without affecting PKM2 stability [ 34 , 37 ]. Viana et al .…”

Section: Discussionmentioning

confidence: 99%

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Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2

Sun

Liu

et al. 2021

Molecular Oncology

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Dysregulation of deubiquitination has been reported to contribute to carcinogenesis. However, the function and mechanism of deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of ovarian cancer (OV), the deadliest gynecological cancer, still remains to be characterized. The present study demonstrated that PSMD14 was overexpressed in OV tissues and its higher levels correlated with a higher International Federation of Gynecology and Obstetrics (FIGO) stage in OV patients. A high level of PSMD14 expression was related to poor survival in OV patients. Knockdown and overexpression experiments elucidated that PSMD14 stimulated OV cell proliferation, invasion, and migration in vitro. Repression of PSMD14 suppressed OV tumor growth in vivo. PSMD14 inhibitor O-phenanthroline (OPA) effectively attenuated malignant behaviors of OV cells in vitro and OV tumor growth in vivo. Mechanistically, we uncovered that PSMD14 was involved in post-translational regulation of pyruvate kinase M2 isoform (PKM2). PSMD14 decreased K63-linked ubiquitination on PKM2, downregulated the ratio of PKM2 tetramers to dimers and monomers, and subsequently diminished pyruvate kinase activity and induced nuclear translocation of PKM2, contributing to aerobic glycolysis in OV cells. Collectively, our findings highlight the potential roles of PSMD14 as a biomarker and therapeutic candidate for OV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2

Sun

Liu

et al. 2021

Molecular Oncology

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“…Parkin mediates the ubiquitination of PKM2 and reduces its enzymatic activity ( Liu et al, 2016 ). Overexpression of cannabinoid receptor-interacting protein 1 (CNRIP1) activates Parkin, leading to PKM2 degradation and thereby promoting cell growth and metastasis in intrahepatic cholangiocarcinoma (ICC) ( Chen D. et al, 2021 ). OTUB2, an OTU deubiquitinating enzyme, directly interacts with PKM2.…”

Section: Ubiquitination Sumoylation and Glucose Metabolism In Cancermentioning

confidence: 99%

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

Zhu

Peng

et al. 2022

Front. Cell Dev. Biol.

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Ubiquitination and SUMOylation, which are posttranslational modifications, play prominent roles in regulating both protein expression and function in cells, as well as various cellular signal transduction pathways. Metabolic reprogramming often occurs in various diseases, especially cancer, which has become a new entry point for understanding cancer mechanisms and developing treatment methods. Ubiquitination or SUMOylation of protein substrates determines the fate of modified proteins. Through accurate and timely degradation and stabilization of the substrate, ubiquitination and SUMOylation widely control various crucial pathways and different proteins involved in cancer metabolic reprogramming. An understanding of the regulatory mechanisms of ubiquitination and SUMOylation of cell proteins may help us elucidate the molecular mechanism underlying cancer development and provide an important theory for new treatments. In this review, we summarize the processes of ubiquitination and SUMOylation and discuss how ubiquitination and SUMOylation affect cancer metabolism by regulating the key enzymes in the metabolic pathway, including glucose, lipid and amino acid metabolism, to finally reshape cancer metabolism.

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“…Previous studies have demonstrated that epigenetic modifications are involved in the development and progression of CRC, altering the gene expression without changing the original DNA sequence ( 6 ). DNA methylation, which is a common epigenetic modification, occurs mainly in promoter regions and often drives gene silencing ( 7 , 8 ). The methylation modifications of specific genes are correlated with the progression of CRC ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma

Qiu

Yang

et al. 2021

Front. Oncol.

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BackgroundGrowing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC.MethodsHIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed.ResultsHIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties.ConclusionOur study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.

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DNA Methylation of Cannabinoid Receptor Interacting Protein 1 Promotes Pathogenesis of Intrahepatic Cholangiocarcinoma Through Suppressing Parkin‐Dependent Pyruvate Kinase M2 Ubiquitination

Abstract: BaCKgRoUND aND aIMS: Methylation landscape is important for maintaining the silence of cannabinoid receptorinteracting protein 1 (CNRIP1) in some tumors. However, the role of CNRIP1 in intrahepatic cholangiocarcinoma (ICC) remains poorly defined.

Cited by 18 publications

References 46 publications

Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2

Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2

Regulation of Glucose, Fatty Acid and Amino Acid Metabolism by Ubiquitination and SUMOylation for Cancer Progression

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma

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