The Protein Kinase Activity of NME7 Activates Wnt/β-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma

Ren, Xinxin; Rong, Zhuoxian; Liu, Xiaoyu; Gao, Jie; Xu, Xu; Zi, Yuyuan; Mu, Yun; Guan, Yifu; Cao, Zhen; Zhang, Yuefang; Zeng, Zimei; Fan, Qi; Wang, Xitao; Pei, Qian; Wang, Xiang; Xin, Haiguang; Li, Zhi; Yingjie, Nie; Qiu, Zilong; Li, Nan; Sun, Lun‐Quan; Deng, Yuezhen

doi:10.1158/0008-5472.can-21-1020

Cited by 21 publications

(19 citation statements)

References 50 publications

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“…MTHFD2 is also a metabolic checkpoint linking purine metabolism to autoimmune responses ( Sugiura et al, 2022 ). It is highly expressed in various cancers, playing a role in metabolic remodeling and regulating of the cell cycle in the mitochondria and nucleus, respectively ( Lee et al, 2021b ; Liu et al, 2021 ; Yao et al, 2021 ; Ren et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

et al. 2022

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Renal cell carcinoma (RCC) is the most common type of renal cancer, characterized by the dysregulation of metabolic pathways. RCC is the second highest cause of death among patients with urologic cancers and those with cancer cell metastases have a 5-years survival rate of only 10–15%. Thus, reliable prognostic biomarkers are essential tools to predict RCC patient outcomes. This study identified differentially expressed genes (DEGs) in the gene expression omnibus (GEO) database that are associated with pre-and post-metastases in clear cell renal cell carcinoma (ccRCC) patients and intersected these with metabolism-related genes in the Kyoto encyclopedia of genes and genomes (KEGG) database to identify metabolism-related DEGs (DEMGs). GOplot and ggplot packages for gene ontology (GO) and KEGG pathway enrichment analysis of DEMGs with log (foldchange) (logFC) were used to identify metabolic pathways associated with DEMG. Upregulated risk genes and downregulated protective genes among the DEMGs and seven independent metabolic genes, RRM2, MTHFD2, AGXT2, ALDH6A1, GLDC, HOGA1, and ETNK2, were found using univariate and multivariate Cox regression analysis, intersection, and Lasso-Cox regression analysis to establish a metabolic risk score signature (MRSS). Kaplan-Meier survival curve of Overall Survival (OS) showed that the low-risk group had a significantly better prognosis than the high-risk group in both the training cohort (p < 0.001; HR = 2.73, 95% CI = 1.97–3.79) and the validation cohort (p = 0.001; HR = 2.84, 95% CI = 1.50–5.38). The nomogram combined with multiple clinical information and MRSS was more effective at predicting patient outcomes than a single independent prognostic factor. The impact of metabolism on ccRCC was also assessed, and seven metabolism-related genes were established and validated as biomarkers to predict patient outcomes effectively.

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Section: Discussionmentioning

confidence: 99%

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

et al. 2022

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“…The tissue array was obtained from Shanghai Outdo Biotech Co., Ltd. IHC staining was performed as previously described [18]. The anti-HMGCL antibody (16898-1-AP, 1:100) was obtained from Proteintech.…”

Section: Immunohistochemical (Ihc) Analysismentioning

confidence: 99%

“…The CCK-8 assay was performed as previously described [18]. Briefly, cells were seeded into a 96-well plate, with 1×10 3 cells in each well, and cultured in an incubator (37 °C, 5% CO 2 ).…”

Section: Cck-8 Assaymentioning

confidence: 99%

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

Zhong¹,

Xiong²,

Yang³

et al. 2023

Int. J. Biol. Sci.

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Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of β-hydroxybutyrate (β-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (Kras G12D ;P53 f/f ) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKβ interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNFα-mediated inflammation and cancer metabolism.

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“…Numerous studies have shown that metabolic reprogramming plays a role in the occurrence and development of tumors as one of the typical malignant features of tumors [1][2][3][4]. During tumor evolution, metabolic pathways are reprogrammed to meet the material and energy demands of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

NAM-NAD+-ADO metabolic reprogramming is a key factor for DNMT3A mutation to promote leukemia development through regulating cell cycle and immune microenvironment

Wang

Yang²,

Wang³

et al. 2022

Preprint

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DNMT3A-R882H mutation is a frequent epigenetic mutation in acute myeloid leukemia (AML)-M4 and M5, participating in the regulation of cell growth and differentiation by blocking the binding of transcription factor complexes to DNA. However, effective approaches that directly target this inactivating mutation for therapy remain lacking. For the first time, we show that the DNMT3A-R882H mutation can switch leukemia cells to undergo nicotinamide (NAM) and nicotinamide adenine dinucleotide (NAD+) metabolism and influence the formation of cyclin-CDK complexes by affecting the deacetylation function of SIRT6. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) can reduce the NAD + required for SIRT6 function, degrade CDKN1A/CDKN1B, and effectively induce cell cycle arrest and apoptosis. The NAMPT inhibitor FK866 can optimize the immune-infiltrating microenvironment by reducing the production of the downstream metabolite adenosine (ADO). Animal experiments have shown that NAMPT inhibition or knockdown can significantly inhibit tumor cell growth, reduce spleen infiltration of tumor cells, and prolong mouse lifespan. Our findings provide a potential direction for a targeted therapy at the metabolic level in AML with DNMT3A mutations.

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The Protein Kinase Activity of NME7 Activates Wnt/β-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma

Cited by 21 publications

References 50 publications

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

Phosphorylation by IKKβ Promotes the Degradation of HMGCL via NEDD4 in Lung Cancer

NAM-NAD+-ADO metabolic reprogramming is a key factor for DNMT3A mutation to promote leukemia development through regulating cell cycle and immune microenvironment

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