m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

Su, Yushan; Liu, Hailing; Luo, Chao; Liang, Huifang; Zhang, Bixiang; Zhang, Wei

doi:10.1186/s12943-023-01841-8

Cited by 27 publications

(9 citation statements)

References 209 publications

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“…As an epitranscriptomic modification, the m6A modification of RNA is widely involved in the regulation of cell renewal and differentiation and metabolism during the progression of various inflammatory and cancerous diseases. 38 However, the specific mechanism by which m6A modification mediates mitochondrial dysfunction under hypoxic gastric condition is still unknown. Therefore, MeRIP‐seq analysis of normal and PHT‐induced gastric mucosa tissues revealed that m6A modification plays an important role in gastric mucosal lesions in PHT.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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IntroductionHypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.ObjectivesTo evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.MethodsPortal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in METTL3 mutant or NLRP3‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.ResultsHIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.ConclusionsUnder hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Xiao,

Liu,

Xie

et al. 2024

Clinical & Translational Med

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“…Not a few excellent studies have discussed the regulatory roles of RNA modifications on metabolism in specified pathological situations, with a particular focus on cancers. 10 – 12 However, there is a deficiency of a comprehensive and wide-scale review on the epigenetic-metabolic interaction covering health and disease context.…”

Section: Introductionmentioning

confidence: 99%

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Liu,

Zheng,

et al. 2024

Sig Transduct Target Ther

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Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

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“…Moreover, increased tumor glycolysis and decreased extracellular pH impede immune cell-mediated targeting of cancer and other therapeutic approaches . Glycolysis levels have been recognized as a criterion for assessing the efficacy of cancer drug therapies. ,− Therefore, evaluating glycolysis is crucial in predicting chemotherapeutic resistance and monitoring treatment outcomes in cancer therapy …”

Section: Introductionmentioning

confidence: 99%

“…2,8−12 Therefore, evaluating glycolysis is crucial in predicting chemotherapeutic resistance and monitoring treatment outcomes in cancer therapy. 13 Currently, biochemistry analyzers and assay kits have been developed to measure extracellular acidification rate and lactate production. 14,15 However, these methods are primarily applicable at the cellular level or in isolated tissue detection.…”

Section: ■ Introductionmentioning

confidence: 99%

“…16−21 However, the short effective half-life and safety concerns hinder its application for long-term dynamic imaging. Similarly, 13 C MRI and deuterium MR imaging have been developed to measure glucose consumption and labeled metabolites, respectively. 22,23 Nevertheless, MRI's relatively low sensitivity limits its ability to detect subtle changes in glycolysis.…”

Section: ■ Introductionmentioning

confidence: 99%

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Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold

Lei,

Yang,

Meng

et al. 2023

J. Am. Chem. Soc.

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Chemotherapeutic resistance poses a significant challenge in cancer treatment, resulting in the reduced efficacy of standard chemotherapeutic agents. Abnormal metabolism, particularly increased anaerobic glycolysis, has been identified as a major contributing factor to chemotherapeutic resistance. To address this issue, noninvasive imaging techniques capable of visualizing tumor glycolysis are crucial. However, the currently available methods (such as PET, MRI, and fluorescence) possess limitations in terms of sensitivity, safety, dynamic imaging capability, and autofluorescence. Here, we present the de novo design of a unique afterglow molecular scaffold based on hemicyanine and rhodamine dyes, which holds promise for low-background optical imaging. In contrast to previous designs, this scaffold exhibits responsive "OFF-ON" afterglow signals through spirocyclization, thus enabling simultaneous control of photodynamic effects and luminescence efficacy. This leads to a larger dynamic range, broader detection range, higher signal enhancement ratio, and higher sensitivity. Furthermore, the integration of multiple functionalities simplifies probe design, eliminates the need for spectral overlap, and enhances reliability. Moreover, we have expanded the applications of this afterglow molecular scaffold by developing various probes for different molecular targets. Notably, we developed a water-soluble pH-responsive afterglow nanoprobe for visualizing glycolysis in living mice. This nanoprobe monitors the effects of glycolytic inhibitors or oxidative phosphorylation inhibitors on tumor glycolysis, providing a valuable tool for evaluating the tumor cell sensitivity to these inhibitors. Therefore, the new afterglow molecular scaffold presents a promising approach for understanding tumor metabolism, monitoring chemotherapeutic resistance, and guiding precision medicine in the future.

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m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

Cited by 27 publications

References 209 publications

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold

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