NNMT‐DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Wu, Changqing; Liu, Yue; Liu, Wenju; Zou, Tian-Hui; Lu, Shaojuan; Zhu, Chengjie; He, Le; Chen, Jie; Lan, Fang; Zou, Lin; Wang, Ping; Fan, Lihong; Wang, Hongxiang; You, Han; Chen, Juxiang; Fang, Jing‐Yuan; Jiang, Cizhong

doi:10.1002/advs.202202642

Cited by 22 publications

(10 citation statements)

References 52 publications

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“…For example, loss of LUC7L2 and U1 snRNP subunits shifts the energy metabolism from glycolysis to OXPHOS 60 . The recent study also demonstrated that cancer cells relying on more OPXHOS are highly expressing DNMT1 and lowly expressing NNMT, by genetically manipulating the expression of NNMT and DNMT1, the sensitivity to OXPHOS inhibitors are changed 61 . Overexpression of NNMT and knockdown of DNMT1 change OXPHOS-inhibition sensitive cell line to be resistant ones, indicating their energy resource reliance shifted from OXPHOS to glycolysis 61 .…”

Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 97%

“…The recent study also demonstrated that cancer cells relying on more OPXHOS are highly expressing DNMT1 and lowly expressing NNMT, by genetically manipulating the expression of NNMT and DNMT1, the sensitivity to OXPHOS inhibitors are changed [61]. Overexpression of NNMT and knockdown of DNMT1 change OXPHOS-inhibition sensitive cell line to be resistant ones, indicating their energy resource reliance shifted from OXPHOS to glycolysis [61]. In the process of energy metabolic switch, the M2 isoform of pyruvate kinase (PKM2, a rate-limiting enzyme in glycolysis) interacts with the key regulator of mitochondrial fusion protein MFN2 to promote the mitochondria fusion and OXPHOS, meanwhile attenuate glycolysis [62], consistently, the activation of MFN2 interacting with PFK1 mediate PFK1 degradation and therefore suppresses glycolysis [63].…”

Section: The Interplay Between Mitochondria and Glycolysismentioning

confidence: 98%

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An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

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Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD + /NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.

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Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 97%

Section: The Interplay Between Mitochondria and Glycolysismentioning

confidence: 98%

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

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“…Reduced histone methylation is a consequence of NNMT's ability to catalyze the methylation of pyridine compounds with S-5′-adenosyl-l-methionine. NNMT is widely expressed in the human body, especially in organs and tissues such as the liver, kidneys, brain, lungs, and adipose tissue, where it is expressed at higher levels [ 48 , 49 ]. The activity and expression levels of NNMT are regulated by various factors, including genetic variations, environmental factors, and nutritional status.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel lipid metabolism-related gene signature to predict outcomes and the tumor immune microenvironment in gastric cancer by integrated analysis of single-cell and bulk RNA sequencing

Zhang,

Wang,

Tian

et al. 2023

Lipids Health Dis

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Gastric cancer (GC) is a pressing global clinical issue, with few treatment options and a poor prognosis. The onset and spread of stomach cancer are significantly influenced by changes in lipid metabolism-related pathways. This study aimed to discover a predictive signature for GC using lipid metabolism-related genes (LMRGs) and examine its correlation with the tumor immune microenvironment (TIME). Transcriptome data and clinical information from patients with GC were collected from the TCGA and GEO databases. Data from GC samples were analyzed using both bulk RNA-seq and single-cell sequencing of RNA (scRNA-seq). To identify survival-related differentially expressed LMRGs (DE-LMRGs), differential expression and prognosis studies were carried out. We built a predictive signature using LASSO regression and tested it on the TCGA and GSE84437 datasets. In addition, the correlation of the prognostic signature with the TIME was comprehensively analyzed. In this study, we identified 258 DE-LMRGs in GC and further screened seven survival-related DE-LMRGs. The results of scRNA-seq identified 688 differentially expressed genes (DEGs) between the three branches. Two critical genes (GPX3 and NNMT) were identified using the above two gene groups. In addition, a predictive risk score that relies on GPX3 and NNMT was developed. Survival studies in both the TCGA and GEO datasets revealed that patients categorized to be at low danger had a significantly greater prognosis than those identified to be at high danger. Additionally, by employing calibration plots based on TCGA data, the study demonstrated the substantial predictive capacity of a prognostic nomogram, which incorporated a risk score along with various clinical factors. Within the high-risk group, there was a noticeable abundance of active natural killer (NK) cells, quiescent monocytes, macrophages, mast cells, and activated CD4 + T cells. In summary, a two-gene signature and a predictive nomogram have been developed, offering accurate prognostic predictions for general survival in GC patients. These findings have the potential to assist healthcare professionals in making informed medical decisions and providing personalized treatment approaches.

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“…For many types of malignancies, the low early detection rate is an obstacle to improved cancer control; 249,250 therefore, efforts to identify novel diagnostic markers are valuable. 251 CD47 has been demonstrated as a diagnostic biomarker for a variety of cancers. It is an innate immune checkpoint and is closely related to the survival in different cancers.…”

Section: Phagocytosis Checkpoints In Diseases and The Tumor Microenvi...mentioning

confidence: 99%

Emerging phagocytosis checkpoints in cancer immunotherapy

Liu

Wang

Yang

et al. 2023

Sig Transduct Target Ther

Self Cite

114

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Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients’ own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as “don’t eat me” signals or interacting with “eat me” signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.

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NNMT‐DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Cited by 22 publications

References 52 publications

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Discovery of a novel lipid metabolism-related gene signature to predict outcomes and the tumor immune microenvironment in gastric cancer by integrated analysis of single-cell and bulk RNA sequencing

Emerging phagocytosis checkpoints in cancer immunotherapy

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