Search

Methionine availability is known to affect the global levels of histone methylation. Here the authors investigate the metabolically driven dynamics of H3K4me3 and find that methionine availability influences peak width, which is linked to changes in expression of genes associated with cell fate and cancer.

Each cell type in the tumour microenvironment has unique metabolic demands enabling specific functions. Here the authors use published single-cell RNA-seq data and develop a computational framework to better understand the heterogeneity of tumour metabolism, highlighting the discordance between results obtained from single cells and bulk tumours.

Methionine restriction decreases fecundity and increases lifespan in flies. Here Wei et al. show that supplementing folic acid, associated with one-carbon metabolism, during methionine restriction in flies, mitigates the decline in fertility while retaining the intervention’s life-extending benefits.

Amino acids are important components in a variety of human foods and diets. Here, the authors show trade-offs linking dietary intake of amino acids to human health and develop amino acid intake guidelines based on them.

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

The hydroxylase EgIN2 contributes to triple negative breast cancers. Here, using an enzyme-substrate trapping strategy, the authors identify ASDL as a bona fide substrate of EgIN2 promoting aggressive properties of TNBC via the activation of cMYC signaling.

Serine synthesis from glucose is required even when serine is available from the environment. Here, the authors explain this paradox by showing that the enzyme PHGDH enables nucleotide synthesis by coordinating anabolic fluxes related to central carbon metabolism, independent of its role in serine production.

Glucose metabolism has long been thought to operate with exquisite specificity and near-optimal efficiency. New findings show, however, that two glycolytic enzymes produce minor products that inhibit other enzymes involved in central carbon metabolism unless they are further metabolized by a novel enzyme.

In two patient-derived xenograft models of colorectal cancer and a mouse model of autochthonous soft-tissue sarcoma, dietary restriction of methionine influences the outcome of cancer and interacts with antimetabolite and radiation therapies, through effects on one-carbon metabolism.

Locasale and co-authors discuss the influence of cellular metabolism on the regulation of chromatin and epigenetics.

This Review reminds us of all those pathways we longed to forget from first year biochemistry: deregulated one-carbon metabolism is a possible driver of oncogenesis. Given the wealth of clinically available agents that target one-carbon metabolism are there opportunities for translation into precision cancer medicine?

The microbiome is implicated in a study that involves the metabolism of dietary fibre into short-chain fatty acids, which provides a biochemical link to the poorly understood histone butyrylation.

Altered DNA methylation is a feature of cancer and between-patient variability is prevalent. Here, the authors integrate data on thousands of human tumours, and find that expression levels of methionine metabolism genes are predictive of methylation features, and that the breakdown of this relationship is a negative prognostic marker.

Torrano et al. use bioinformatics analyses to identify PGC1α as a transcriptional regulator of a metabolic program downstream of ERRα that opposes metastatic dissemination in prostate cancer.

The molecular determinants of differential responses of different cancer cells to methionine restriction are poorly understood. Here the authors show that hepatocyte nuclear factor 4α regulates sulfur amino acid metabolism and dictates the sensitivity of liver cancer to this dietary manipulation.

The mechanistic target of rapamycin complex 1 (mTORC1) network integrates nutrient and energy signals that regulate metabolism and cell growth. Orozco et al. now show that the glycolytic intermediate dihydroxyacetone phosphate (DHAP) relays glycolytic activity to mTORC1 signalling.

The metabolite methylthioadenosine (MTA) inhibits PRMT5. Therefore, MTA accumulation due to MTA phosphorylase (MTAP) deletion has been proposed as a vulnerability for PRMT5-targeted therapy in cancer. Here, the authors show that MTA does not accumulate in MTAP-deficient cancer cells but is secreted and metabolized by MTAP-intact cells in the tumour microenvironment.

Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.

Myeloid-derived suppressor cells (MDSCs) occupy sites of chronic inflammation and suppress CD8⁺ T cell function. A new study describes the transfer of the metabolite methylglyoxal (MG) to T cells, which mediates this immunosuppressive mechanism.

Fruitflies require Sestrin to regulate mTORC1 signalling in response to dietary leucine, survive a diet low in leucine, and control leucine-sensitive physiological characteristics, which establishes Sestrin as a physiologically relevant leucine sensor.

The glycolytic enzyme pyruvate kinase M2 (PKM2) is required for nucleotide synthesis and cell proliferation. Using gene expression and metabolomics analyses, the authors here show that PKM2 regulates methionine metabolism and DNA methylation in endothelial cells.

Formaldehyde, a DNA-damaging agent formed in cells, has now been shown to support metabolic processes that involve molecular units containing a single carbon atom — linking metabolism to a DNA-protection mechanism. See Article p.549

Zhang, Fang, et al. develop a method to perform an in-depth lysine succinylation analysis in the mouse liver. This approach allows them to identify a previously unappreciated mechanism of regulation of the urea cycle and ammonia detoxification.

The gut microbiota can alter the effects of anticancer fluoropyrimidines such as 5-fluorodeoxyuridine (FUdR) in the model organism C. elegans. Here, the authors show that these effects are further affected by diet, and dietary thymidine and serine increase FUdR toxicity in C. elegans via different mechanisms.

Seemingly unrelated mutations that drive cancer share the ability to promote nutrient uptake and metabolism conducive to cell growth.

Neural stem and progenitor cells (NSPCs) encounter constant stresses during aging, such as elevated oxidative stress. Here the authors show that oxidative stress induced reduction in NSPC neural differentiation is mediated by a FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signalling cascade initiated by FOXO3 oxidation.

Horng and colleagues show that mitochondrial glycerol-3-phosphate dehydrogenase, a component of the glycerol phosphate shuttle, modulates a shift from inflammation to immunosuppression in activated macrophages.

Davis et al. demonstrate heterogeneous and distinct transcriptome programs in breast cancer micrometastasis associated with upregulated mitochondrial oxidative phosphorylation.

Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes.

CRISPR–Cas9 knockout screens in chemotherapy-treated acute myeloid leukemia cells help map the drug-dependent genetic basis of fitness trade-offs (antagonistic pleiotropy) for the design of evolutionary traps that target drug resistance in cancer.

Consistent crosstalk between cancer cells and stromal cells exists in the tumour microenvironment. Yan et al. show that exosomal miR-105 derived from cancer cells confers metabolic plasticity in recipient cancer-associated fibroblasts to adapt to nutrient-replete and -deplete conditions, thereby sustaining tumour growth.

Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.

MNK2 was identified as the target of a small molecule named CID661578 that can stimulate pancreatic β-cell generation in zebrafish, pig and human organoids. CID661578 prevents MNK2 from binding to eIF4G in the translation initiation complex.

Tumor-associated macrophages support an immunosuppressive tumor microenvironment. Di Conza et al. uncover how IRE1–XBP1 and IRE1−STAT3 endoplasmic reticulum stress responses pathways are engaged by tumor-derived lipids to orchestrate pro-tumorigenic features and survival in tumor-associated macrophages.

Tumour recurrence is a common cause of death for patients with cancer. Here Fox et al. show how the antioxidant transcription factor Nrf2 is activated in dormant residual tumour cells and promotes their proliferation and tumour growth by inducing a metabolic reprogramming aimed to maintain redox homeostasis and nucleotide synthesis.

Ho and colleagues report that mitochondrial dysfunction and impaired mitophagy triggered by the tumor microenvironment lead to subsequent epigenetic changes and cause permanent T cell exhaustion and dysfunction.

T cells undergo metabolic reprogramming after they are activated. Rathmell and colleagues show that inflammatory Toll-like receptor signals induce glycolysis and impair the suppression of regulatory T cells, but Foxp3 can promote a switch to oxidative phosphorylation and suppression.

The pathomechanism of succinyl-CoA ligase (SCL) deficiency, a hereditary mitochondrial disease, is not fully understood. Here, the authors show that increased succinyl-CoA levels contribute to SCL pathology by causing global protein hyper-succinylation.

Post-translational modifications are one way in which GTPase functions can be regulated. Monoubiquitination of Lys147 of Ras has been shown to promote tumorigenesis. New data now indicate that this modification promotes Ras activation by impairing GTP hydrolysis catalyzed by GTPase-activating proteins.

Pan et al. find that regional glutamine deficiency in melanoma tumours induces tumour cell dedifferentiation and confers therapeutic resistance through histone methylation changes.

Brain tumor initiating cells (BTICs) utilize high-affinity glucose uptake, which is normally active in neurons to maintain energy demands and self-renew. Leveraging metabolomic and genomic analyses, Wang et al. report that de novo purine biosynthesis reprograms BTIC metabolism, revealing a potential point of fragility amenable to targeted cancer therapy.

The authors previously showed that mTOR controls the function of regulatory T cells. Here they show how this mTOR signaling orchestrates homeostasis of T_reg-cell subsets and prevents fatal autoimmunity.

Andrew Feinberg, Christine Iacobuzio-Donahue and colleagues describe the epigenomic reprogramming that occurs during pancreatic cancer progression. They also show that hematogenous metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP) and that oxPPP inhibition reverses chromatin reprogramming and blocks tumorigenic potential.

Analysis of gene expression data from 22 tumor types reveals differences in how the metabolic network is perturbed in cancer.