Methionine Restriction and Tumor Epigenetics
I. Tumor Epigenetics
As we ask the question, initially, what causes the cancer cells to become cancerous? The answer to this has been certain for the last decades. Genetic alteration in a single cell causes it to proliferate abnormally. Further mutations accumulate in the expanding cell population, leading to genetic heterogeneity clones that compete through further proliferation, becoming increasingly virulent, culminating in metastasis. So cancer is, first and last, from its initiation to metastasis, a matter of genetic alterations. It is known as the somatic mutation theory (SMT) of cancer. After the advent of SMT, more than a hundred human oncogenes have been discovered. Following that, more than thirty tumor suppressor genes have been identified accordingly, as their name implies that these genes suppress cell proliferation. Mutations in tumor suppressor genes cause them to be less suppressive.
Recently, an alternative to cell dedifferentiation theory (CDT) has been proposed. From this point of view, cancer cells are actually derived from somatic stem cells gone bad under some environmental pressure. After their birth, they took a wrong turn, converting from normal somatic stem cells to cancer stem cells. These cancer stem cells undergo asymmetric cell division, resulting in one cancer stem cell and one more differentiated cancer cell. The differences between the dedifferentiation and stem cell of cancer working in both ways: one side, cancer cells move backward toward stemness to dedifferentiate; on the other side, the cells move forward from stemness to over-differentiate (Joseph D. Butneret al., 2022). The two groups of cancer are not mutually exclusive. From this perspective, the goal of any therapeutic intervention should be to knock out the relatively few cancer cell stemness.
The switch of dedifferentiation and stemness of cancer cells are the typical cellular epigenetic characterizations, thus leading to a proposal of tumorigenesis. Tumor formation can occur not only through gene mutations but also via epigenetic mechanisms that the morphological/pathophysiological transformation occurs without change of the underlying DNA sequence.
One original publication of melanoma onset in mice can be accelerated by modifier genes normally present in other mouse strains. This gene codes for an RNA-binding protein that is involved in cell cycle arrest, apoptosis, and cell migration and invasion. How the environment can lead to cancer by triggering large-scale physiological changes that precede gene mutations, was unknown. (Ferguson B, 2019)
The recent report published in Nature by Giacomo Cavalli team (Parreno, et al, 2024) that perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. The link to the irreversible derepression of genes that can drive tumorigenesis, involved in members of the JAK–STAT signaling pathway and zfh1, the fly homologue of the ZEB1 oncogene. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumors can emerge through epigenetic dysregulation.
Overall, this perspective highlights a more dynamic view of cancer development, emphasizing the interplay between genetic and environmental factors, where environmental stresses can trigger irreversible changes in cells that ultimately lead to cancer. ( Douglas E Brash, 2019 ).
II. Methionine as one carbon metabolism in epigenetic regulation
Methionine, an essential amino acid, is a breakdown product from protein food in the small intestine. The free methionine is absorbed and used for protein synthesis and into the Methionine cycle to generate S-adenosylmethionine (SAM) through the adenylation of Methionine by Methionine adenosyltransferase. SAM is considered the universal methyl donor and is used by methyltransferases to methylate metabolites, RNA, DNA, and proteins, including histones. SAM acts as a major methyl and sulfate group donor for generation of Glutathione, Sam also directs formation of polyamines for cell proliferation shown in Figure 1. (From Wanders et al, Nutrients 2020 ).
Figure 1. Methionine metabolism and major functions with relevance to GSH biosynthesis, Cell proliferation and methylation. GSH: Glutathione; MAT: Methionine adenosyltransferase; SAM: S-adenosylmethionine. ( From Wanders et al, Nutrients. 2020 ).
By the transsulfuration pathway for deactivating radicals and reactive oxidants, Glutathione participates in thiol protection and redox regulation under oxidative stress pressure. Glutathione synthesis buffers oxidative stress, thereby creating a dependence on exogenous Methionine. In Cancer cells the need to divert homocysteine from the Methionine cycle into the transsulfuration pathway have shown the exogenous Methionine dependence.
The addition of methyl groups from Methionine, as one carbon metabolism, to the cytosine residues in CpG islands in the promoter region of tumor suppressor genes can silence their expression (Newell-Price, et al., 2000). This prevents the activation of tumor suppressor functions, such as cell cycle regulation and apoptosis. Tumor suppressor gene p16INK4a is frequently silenced in various cancers due to promoter hypermethylation (Rocco JW, Sidransky D, 2001). Conversely, global DNA hypomethylation or demethylation of specific genes activate oncogenes, leading to uncontrolled cell growth.
Histone acetylation and deacetylation influence the expression of genes involved in tumorigenesis, and Histone deacetylase (HDAC) inhibitors can prevent the silencing of tumor suppressor genes. Meanwhile, one carbon metabolism that guarantees the Lysine methylation in Histone can either activate or repress gene expression, depending on the specific histone residue that is methylated. Epigenetic disruptions such as global reductions in methylation, which are often present before any known mutations in oncogenes, causes the instability in the chromosomes, as well as increases in oncogene expression (Deroo LA, et al., 2014). While tumor suppressor genes are hyper-methylated in suppressing the tumor suppressors (Hu M, et al., 2005). Chromatin remodeling proteins, such as those in the SWI/SNF complex, can influence the accessibility of DNA to the transcriptional machinery (Stern M, et al., 1984).
Cancer stem cells can undergo epigenetic reprogramming, without requiring mutations in the DNA sequence. These epigenetic modifications alter the expression of key genes that control cell growth and apoptosis, which will result in uncontrolled cell proliferation, tumor formation and metastasis. This expression patterns have changed through DNA methylation, histone modifications, and non-coding RNAs, allowing these cells to maintain their stem-like properties and resistance to conventional therapies.
As our understanding of epigenetics advances, it may open up new possibilities for early detection, prevention, and treatment of cancer, potentially through the reversal of epigenetic modifications.
III. Methionine restriction in tumorigenesis?
Methionine restriction (MR), through reduced available SAM, decreases the histone methylation of H3K4me2, H3K4me3, H3K9me2, and H3K27me3 (Tang X, et al., 2015). During times of low SAM availability, both di- and tri-methyl histone marks are preferentially removed while H3K9 mono-methylation marks are preserved to maintain heterochromatin stability, suggesting H3K9 mono-methylation is necessary for a cell to maintain its heterochromatin state (Haws SA, et al., 2020). DNA hypomethylation in cancer is also associated with gene silencing due to the formation of repressive chromatin structures at these sites (Bachman KE, et al., 2003).
The most abundant modification of eukaryotic mRNA is methylation of adenosine by guanine 7-methyltransferase, which uses SAM to create the 5’-methyl cap on pre-mRNA, where eukaryotic initiation factor 4α (eIF4α) binds and recruits the 40S ribosomal subunit to begin translation and control m6A-dependent mRNA decay (Ramirez CV, et al., 2002). Additionally, SAM is recruited for RNA modifications to generate functional mRNA and control tRNA base-pairing (Laxman S, et al., 2013). MR may preferentially affect cancer cells that require mRNA methylation to generate mature mRNA transcripts and may depend more heavily on tRNA uridine modifications to translate damaged mRNA transcripts, which contribute to translation inhibition in cancer cells in response to methionine limitation.
While normal cells can adapt to lower methionine levels by utilizing alternative pathways (like homocysteine), cancer cells are often less capable of such metabolic flexibility. This difference could make cancer cells more vulnerable to methionine restriction than healthy cells. Strict methionine limitation will help to kill tumor cells from methionine starvation.
Although animal studies are promising, human trials investigating methionine restriction as a cancer therapy are still in early stages. The precise effects, optimal dietary protocols, and safety for long-term use are still being studied. Thus, any potential therapeutic use of MR must carefully balance cancer treatment with overall nutritional needs. Methionine restriction may be most effective when used in conjunction with other therapies, such as chemotherapy. More research is needed to fully understand its role in cancer treatment on the matter of how the genetic mutation and microenvironment works mutually and independently.
One prominent version of the epigenetic view touts the stem cell theory of cancer dynamics. Carcinogens for the cause of DNA mutation, are something that alter epigenetic regulation, which broadens that category considerably relative to somatic mutation theory. The therapeutic implications are also strikingly different because epigenetic processes, unlike genetic processes, are reversible. There are also more ways to intervene epigenetically, and research in the development of epigenetic therapies is booming. One potential advantage over most therapies used currently is that they can be much more fine-tuned, compromising fewer healthy cells.
IV. The availability of MR in the next generation
The future food is shaped by several key trends of technological advancements, environmental concerns, and consumer preferences. As people become more conscious of sustainability and health, the demand for plant-based proteins and alternative protein sources (like lab-grown meat, yeast extract products ) will grow to replicate the taste, texture, and nutritional benefits of animal products. Established industries will topple because of the old models of agriculture of traditional animal farming. New food will be reciped to the demand for offering health benefits beyond basic nutrition (e.g., probiotic-rich foods, functional snacks, and nutraceuticals). These foods aim to improve immunity, gut health, brain function, and overall well-being. Lab-grown meat and dairy products, made from cultured cells, such as yeast extract with low methionine level are poised to become more mainstream. Healthy conditions to reduce food-induced diseases such as obesity, diabetes, cardio-vascular disorders, brain strokes. and more, prophylaxis and treatment of cancers. The continuation and extension of the trends will be in appliance of the novel tumor epigenetics to decrease cancer incidence and extend lifespan.
Genetic mutation of DNA and epigenetic environment both work hand in hand for tumor development, the goal of the treatment of the disease is not only to kill the tumor cell but to transform the cell, in reversion of the tumor cell into normal. As for the methionine restriction in participation of epigenetic regulation, surveillance methylation level of histone protein, DNA and RNA, gene-expression status, the stemness and differentiation, are necessary. Advances in genomics and data analytics will enable food to be tailored to an individual’s unique dietary needs, health conditions, and genetic makeup and supplements that cater specifically to one's health profile. Combining the crispr and gene edit will target and reverse the mutation sites on the oncogene and tumor suppressor genes.
Change is inevitable, even though much of this alteration is imperceptible. This never-ending change is the pivotal axis of the modern world, a continuously updated sequence of materials rapidly adapting to customer usage, feedback, competition. Any vigilant, eyes-wide-open promises work to change so much that we can embrace them. Only by working with these technologies can we gain the best of what they have to offer. The use of AI, nanoparticle technologies, and smart appliances will revolutionize how effective medical supervision is on cancer types with individual patient factors. Additionally, dietary interventions undertaken, like methionine restriction, can have effects on both mutually intertwined accounts in genetic and epigenetic cancer therapeutics.
References Omitted
Written by Dr. Haining Jin, and Dr. Bin Xu
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