NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis

Guo, Haoyan; Xu, Jiaqian; Zheng, Quan; He, Jianli; Wei, Zhou; Wang, Kezhou; Huang, Xian; Fan, Qiuju; Ma, Jiao; Cheng, Jinke; Mei, Wenhan; Rong, Xing; Cai, Rong

doi:10.1016/j.canlet.2019.09.010

Cited by 45 publications

(38 citation statements)

References 45 publications

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“…Post-translational modifications of proteins, such as ubiquitination and phosphorylation, play an important role in this process. For example, changes in the level of nuclear factor erythroid 2-related factor 2 (Nrf2) SUMOylation affect the intracellular ROS level and thus the autophagy level of cells, which ultimately affect the occurrence and development of hepatocellular carcinoma [10].…”

Section: Introductionmentioning

confidence: 99%

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Liu

Feng

et al. 2020

J Exp Clin Cancer Res

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Background: 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. Methods: Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. Results: BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt Ser473 and mTOR Ser2448. Conclusions: Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

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Section: Introductionmentioning

confidence: 99%

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Liu

Feng

et al. 2020

J Exp Clin Cancer Res

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“…Currently, accumulating evidence has proved that targeted therapies may effectively treat HCC patients. 37 , 38 However, the rapid development of drug resistance weakened the clinical effects of targeted drugs. Thus, it is urgent to develop more novel HCC biomarkers and treatment strategies in HCC patients.…”

Section: Discussionmentioning

confidence: 99%

A miR-212-3p/SLC6A1 Regulatory Sub-Network for the Prognosis of Hepatocellular Carcinoma

Zhang

Wang²,

et al. 2021

CMAR

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Introduction Hepatocellular carcinoma (HCC) is a liver cancer with a poor prognosis. Owing to the complexity and limited pathogenic mechanism research on HCC, the molecular targeted therapy has been hindered. Methods In this study, we categorized transcriptome data into low-Myc and high-Myc expression groups in 365 HCC samples, screened the differentially expressed RNAs, including 441 DE-lncRNAs, 99 DE-miRNAs and 612 DE-mRNAs, constructed a lncRNA-miRNA-mRNA regulatory network, and selected a hub triple regulatory network through cytoHubba analysis. Through Gene ontology and KEGG pathway, a hub regulatory network was particularly enriched in the “Wnt signaling pathway” and “Cytochrome P450-arranged by substrate type” by Metascape. The prognostic genes in the hub regulatory network were evaluated by the RNA expression analysis, Kaplan–Meier (KM) survival analysis, and correlation analysis. Results The results showed that miR-212-3p/SLC6A1 axis was a potential prognostic model for HCC. Furthermore, IHC analysis showed down-regulated expression of SLC6A1 in HCC tissues and Alb-Cre;Myc mouse liver cancer tissues. The genetics and epigenetic analysis indicated that SLC6A1 expression was negatively correlated with DNA methylation. Immune infiltration analysis showed a negative relation between SLC6A1 and T cell exhaustion/monocyte in liver cancer tissues. Conclusion In summary, the study revealed that miR-212-3p/SLC6A1 axis could serve as a crucial therapeutic target for HCC.

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“…These reactions demonstrate that the SSP metabolic enzymes have a significant impact on the production of the one-carbon unit. By depleting the availability of the one-carbon unit, serine starvation or downregulation of SSP metabolic enzymes causes the reduction of cancer cell proliferation and xenograft growth (80)(81)(82). Additionally, glycine, similarly to serine, can also be a source of the one-carbon unit through the GCS, although this reaction only occurs within the mitochondria and fuels one-carbon metabolism (83).…”

Section: Inputs and Outputs Of One-carbon Metabolismmentioning

confidence: 99%

Serine, glycine and one‑carbon metabolism in cancer (Review)

et al. 2020

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NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis

Cited by 45 publications

References 45 publications

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

A miR-212-3p/SLC6A1 Regulatory Sub-Network for the Prognosis of Hepatocellular Carcinoma

Serine, glycine and one‑carbon metabolism in cancer (Review)

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