Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP Jr, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW.
Nature. 2019 Aug;572(7769):397-401
Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.
Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Dai Z, Mentch SJ, Gao X, Nichenametla SN, Locasale JW
Nat Commun 2018 May;9(1):1955
Nutrition and metabolism are known to influence chromatin biology and epigenetics through post-translational modifications, yet how this interaction influences genomic architecture and connects to gene expression is unknown. Here we consider, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyze the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability in both normal mouse physiology and human cancer cells. Surprisingly, we find that the location of H3K4me3 peaks is largely preserved under methionine restriction, while the response of H3K4me3 peak width encodes almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer-associated genes. These findings may reveal general principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate biological function.
One of the negative aspects of aging is the decreased ability to maintain normal cellular functions, which eventually manifests as disease. Optimal maintenance of DNA methylation is critical for normal cellular functions, but, as organisms age, the number of methyl groups on DNA drops. This may result in the development of disorders such as cancer, impaired glucose/lipid metabolism, and cardiovascular diseases.
The two major dietary sources of methyl groups in animals are methionine and choline. Past research has shown that rats and mice fed diets low in methionine (MR) but optimal in choline are less susceptible to aging-associated diseases and outlive mice on regular diets. In this study, Senior Scientist Dr. Sailendra Nichenametla and his team hypothesized that an MR diet induces changes in DNA methylation, which ultimately contributes to its beneficial effects. Dr. Nichenametla investigated this hypothesis in mice of two different ages (young and adult) by feeding each either a control diet (normal levels of choline and methionine; CF) or an MR diet (normal choline levels, but 80% less methionine).
Findings from this study suggest that an MR diet, despite containing comparatively fewer methyl groups, prevents loss of DNA methylation in the liver. While seeming paradoxical, these findings are plausible and highlight the complexity of biological systems. A decrease in a number of methyl groups coming from methionine may not have an effect because of the presence of choline, which also contributes to methyl groups. However, the MR diet results in lower levels of S-adenosylhomocysteine (SAH). Previous studies found that SAH levels increase during aging.
Here at OFAS, we strive to provide insight into the mechanistic basis of lifespan extension by MR diet through our research. Based on our findings, we conclude that an MR diet improves the efficiency of DNA methylation maintenance systems in adult mice, but has no effect in young mice, likely due to the fact that young animals already have lower levels of SAH compared to adult mice. With this study, we are one step closer to finding ways to slow down the process of aging-associated diseases such as cancer.
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