Methyl Group Metabolism in Differentiation, Aging, and Cancer

Abstract

Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the successful conversion of dietary nutrients into the basic building blocks to carry out any cellular methylation reaction. Methyl groups play essential roles in numerous cellular functions such as DNA methylation, nucleotide- and protein biosynthesis. Especially, DNA methylation is responsible for organizing the genome into transcriptionally silent and active regions. Ultimately, it is this proper annotation that determines the quality of expression patterns required to ensure and shape the phenotypic integrity and function of a highly specialized cell type. Life is characterized by constantly changing environmental conditions, which are addressed by changes in DNA methylation. This relationship is increasingly coming into focus as it is of fundamental importance for differentiation, aging, and cancer. The stability and permanence of these metabolic processes, fueling the supplementation of methyl groups, seem to be important criteria to prevent deficiencies and erosion of the methylome. Alterations in the metabolic processes can lead to epigenetic and genetic perturbations, causative for diverse disorders, accelerated aging, and various age-related diseases. In recent decades, the intake of methyl group compounds has changed significantly due to, e.g., environmental pollution and food additives. Based on the current knowledge, this review provides a brief overview of the highly interconnected relationship between nutrition, metabolism, changes in epigenetic modifications, cancer, and aging. One goal is to provide an impetus to additionally investigate changes in DNA methylation as a possible consequence of an impaired methyl group metabolism.

Impedance-based assay for pan-cancer early and rapid detection of cell-free DNA

“…It is the presence of these non-polar functional groups that likely leads to the hydrophobic self-assembly of healthy cfDNA in aqueous solution. As the loss of methyl groups from the cytosines happens gradually during cancer 34 , the morphology changes from microaggregates to dispersed nanoaggregates as the cancer progresses, which is made evident by the stage-wise TEM images of the cfDNA samples shown in Fig. 2G.…”

Amino acid metabolism, redox balance and epigenetic regulation in cancer

“…SAM, as the universal methyl donor, not only can be utilized for DNA and histone methylation, but also is critical for RNA methyltransferases to sustain RNA methylation, which includes RNA splicing, processing, translation and degradation, and associates with tumorigenesis and metastasis [102]. As the inhibitor of several methyltransferases, the increased concentration of SAH may result in global hypomethylation [103]. Consequently, the SAM/SAH ratio is tightly linked with regulated epigenetic modification and has become a reference of methylation potential [104].…”

“…Indeed, SAM/SAH ratio also can be directly altered by the availability of methionine via methionine metabolism, resulting in a series of robust changes in methylation. When the intracellular methionine level is relatively high, which results in SAM abundance, the conversion of homocysteine to methionine is limited and diverted into transsulfuration by inhibiting MTHFR and betaine homocysteine methyltransferase and activating CBS via SAM [103]. Under methionine deficiency conditions, cancer cells tend to selectively overexpresses MAT2A in an effort to sustain cellular SAM levels.…”

Rescue of Methionine Dependence by Cobalamin in a Human Colorectal Cancer Cell Line

“…Similarly, repressive histone methylation marks are decreased globally and increased in tumor suppressor genes. Methionine is also a precursor for the antioxidant glutathione through the transulfuration pathway (reviewed in [11,12]). Consequently, methionine and its associated metabolites play a crucial role in carcinogenesis and cancer progression.…”