Metabolic reprogramming and epigenetic modifications on the path to cancer

Protein & Cell, Journal Year: 2021, Volume and Issue: 13(12), P. 877 - 919

Published: May 29, 2021

Abstract Metabolic rewiring and epigenetic remodeling, which are closely linked reciprocally regulate each other, among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes a consequence translocation spatial regionalization metabolites. Various metabolic alterations modifications also reportedly drive immune escape impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how reprogramming cells reshapes alterations, particular acetylation methylation histone proteins DNA. We discuss other eminent such as, succinylation, hydroxybutyrylation, lactylation, update current advances metabolism- modification-based therapeutic prospects cancer.

Language: Английский

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Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 14, 2021

Abstract Many tumour cells show dependence on exogenous serine and dietary glycine starvation can inhibit the growth of these cancers extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression de novo synthesis pathway (SSP) enzymes or activation oncogenes that drive synthesis. Here we inhibition PHGDH, first step SSP, cooperates with depletion one-carbon metabolism cancer growth. In vitro, PHGDH combined leads a defect global protein synthesis, which blocks an ATF-4 response more broadly impacts protective stress amino acid depletion. vivo, combination diet inhibitor shows efficacy against tumours are resistant drug alone, evidence reduced availability. ATF4-response seen vitro following complete available is not mice, where treatment lower but do eliminate serine. Our results indicate will augment depleted diet.

Language: Английский

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Comprehensive metabolomics expands precision medicine for triple-negative breast cancer

Cell Research, Journal Year: 2022, Volume and Issue: 32(5), P. 477 - 490

Published: Feb. 1, 2022

Abstract Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome 330 TNBC samples 149 paired normal tissues to construct large metabolomic atlas TNBC. Combining with previously established transcriptomic genomic data same cohort, we conducted comprehensive analysis linking genomics. classified TNBCs into three distinct subgroups: C1, characterized by enrichment ceramides fatty acids; C2, featured upregulation related oxidation reaction glycosyl transfer; C3, having lowest level metabolic dysregulation. Based on this newly developed dataset, refined previous subtypes identified some crucial subtype-specific as potential therapeutic targets. The luminal androgen receptor (LAR) subtype overlapped C1 subtype. Experiments patient-derived organoid xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate ceramide pathway, promising therapy for LAR tumors. Moreover, basal-like immune-suppressed (BLIS) contained two prognostic subgroups (C2 C3), which could be distinguished through machine-learning methods. We show N-acetyl-aspartyl-glutamate tumor-promoting metabolite target high-risk BLIS Together, our reveals clinical significance metabolomics, can not only optimize subtyping system, but also suggest novel This dataset serve useful public resource promote precision treatment

Language: Английский

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Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis

Metabolites, Journal Year: 2021, Volume and Issue: 11(1), P. 28 - 28

Published: Jan. 2, 2021

Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of primary site, intravasation into vessels where anchorage-independent is required, colonization distant organs environment distinct from that site. Thus, cancer must reprogram their state every step progression. Metabolic reprogramming now recognized as a hallmark supports growth. Elucidating underlying mechanisms may help identifying targets treatment strategies. This review summarizes our current understanding progression metastasis, cell adaptation to microenvironment, defense against oxidative stress vessels, metastasis.

Language: Английский

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The ins and outs of serine and glycine metabolism in cancer

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(2), P. 131 - 141

Published: Jan. 28, 2021

Language: Английский

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SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 15, 2021

Abstract The recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of COVID-19 pandemic. How this novel beta-coronavirus virus, and coronaviruses more generally, alter cellular metabolism to support massive production ~30 kB viral genomes subgenomic RNAs remains largely unknown. To gain insights, transcriptional metabolomic analyses are performed 8 hours after SARS-CoV-2 infection, an early timepoint where lifecycle completed but prior overt effects on host cell growth or survival. Here, we show that remodels folate one-carbon at post-transcriptional level de novo purine synthesis, bypassing shutoff translation. Intracellular glucose depleted in SARS-CoV-2-infected cells, replication exquisitely sensitive inhibitors metabolism, notably methotrexate. Host targeted therapy could add armamentarium against future coronavirus outbreaks.

Language: Английский

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Methionine deficiency facilitates antitumour immunity by altering m⁶A methylation of immune checkpoint transcripts

Gut, Journal Year: 2022, Volume and Issue: 72(3), P. 501 - 511

Published: July 8, 2022

Objective Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA antitumour immunity are molecularly intertwined. Design The effect methionine-restricted diet (MRD) feeding was assessed murine models. mechanisms YTH domain-containing family protein 1 (YTHDF1) tumour immune escape were determined vitro vivo. synergistic effects MRD or YTHDF1 depletion with PD-1 blockade also investigated. Results We found that dietary restriction reduced growth enhanced by increasing the number cytotoxicity tumour-infiltrating CD8 + T cells different mouse Mechanistically, S-adenosylmethionine derived from promoted N 6 -methyladenosine (m A) translation checkpoints, PD-L1 V-domain Ig suppressor cell activation (VISTA), cells. Furthermore, m A-specific binding inhibited restoring infiltration cells, synergised for better control. Clinically, expression correlated poor prognosis immunotherapy outcomes cancer patients. Conclusions play critical role anticancer through regulating functions Targeting could be potential new strategy immunotherapy.

Language: Английский

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Moonlighting functions of metabolic enzymes and metabolites in cancer

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(18), P. 3760 - 3774

Published: Sept. 1, 2021

Language: Английский

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Recent advances in metabolomics analysis for early drug development

Drug Discovery Today, Journal Year: 2022, Volume and Issue: 27(6), P. 1763 - 1773

Published: Feb. 24, 2022

The pharmaceutical industry adapted proteomics and other 'omics technologies for drug research early following their initial introduction. Although metabolomics lacked behind in this development, it has now become an accepted widely applied approach development. Over the past few decades, evolved from a pure exploratory tool to more mature quantitative biochemical technology. Several metabolomics-based platforms are during phases of discovery. Metabolomics analysis assists definition physiological response target engagement (TE) markers as well elucidation mode action (MoA) candidates under investigation. In review, we highlight recent examples novel developments analyses

Language: Английский

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Insulin-regulated serine and lipid metabolism drive peripheral neuropathy

Nature, Journal Year: 2023, Volume and Issue: 614(7946), P. 118 - 124

Published: Jan. 25, 2023

Abstract Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves 1,2 . Although the onset progression these co-morbidities are linked with insulin resistance, hyperglycaemia dyslipidaemia 3–7 , aberrant non-essential amino acid (NEAA) metabolism also contributes to pathogenesis diabetes 8–10 Serine glycine closely related NEAAs whose levels consistently reduced patients syndrome 10–14 but mechanistic drivers downstream consequences this metabotype remain unclear. Low systemic serine emerging as hallmark macular nerve disorders, correlating impaired visual acuity neuropathy 15,16 Here we demonstrate that homeostasis drives deficiencies diabetic mice, can be diagnosed tolerance test quantifies uptake disposal. Mimicking alterations young mice by dietary or restriction together high fat intake markedly accelerates small fibre while reducing adiposity. Normalization supplementation mitigation myriocin both alleviate linking serine-associated sphingolipid metabolism. These findings identify deficiency novel risk factors for may exploited therapeutically.

Language: Английский

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