Introduction-
Both obesity and cancer are complex medical conditions that are considered public health problems. Epidemiological studies have shown that lifestyle factors may play a key role in carcinogenesis. In this article, Eduardo Izquierdo-Torres and his team at the National Autonomous University of Mexico have performed a search in the literature of studies where high-fat and high-carb diets were evaluated for their role in modulating gene expression of key genes involved in cancer development and progression.
Research-
Obesity and it’s risk factors-
Obesity is a chronic, multifactorial and neurobehavioral disease due to an excessive accumulation of adipose tissue secondary to an imbalance between the energy obtained from eating high-calorie foods and the energy consumed. The main risk factor here is excessive food intake, with poor energy expenditure (sedentary lifestyle), which in the last year has increased due to SARS-CoV-2 pandemic. Diet and obesity can contribute to cancer which is basically a multifactorial disease involving several risk factors to tumor initiation and progression.
Fig 1- Risk factors associated with obesity and cancer initiation and progression
Epigenetics: The link between diet and gene expression
Epigenetics is the study of molecules and mechanisms that can perpetuate alternative gene activity stated in the context of the same DNA sequence. One of the main features of epigenetic mechanisms is that they are reversible due to the ability that organisms must have to adapt to changing environmental conditions, which promotes the study and design of therapies based on their modulation. Epigenetic mechanisms involve DNA methylation, histone post-translational modifications (PTM), non-coding RNAs, nucleosome remodeling, and histone variants.
In colonic mucosa, High fat diet (HFD) increases the expression of the FXR gene by decreasing the methylation at its promoter and decreases the expression of the APC gene by increasing the methylation at its promoter. In mice exposed to HFD in utero, the combined treatment of the DNA methyltransferase inhibitor (DNMTi) hydralazine and the histone deacetylase inhibitor (HDACi) valproic acid, reduces mammary tumor multiplicity, decreases DNMT3a expression, and increases the expression of the tumor suppressor gene Cdkna2a/p16. However, in mice that were not exposed to HFD, these epigenetic inhibitors increased mammary tumor incidence and burden. In prostate cancer, HFD is associated with the hypomethylation of H4K20 at the MYC regulated genes, resulting in sustained cell proliferation and tumor burden.
Figure 2- Cytosine methylation and demethylation mechanism
An important mechanism that regulates the function of eukaryotic genomes is post-translational modifications (PTMs) of histone proteins. Histones form nucleosomes, which are enveloped by DNA. Acetylation of lysine residues present in the outer tails of histones H3 and H4 tends to reduce interactions between DNA and nucleosomes, allowing access to the transcription machinery. The opposite reaction, histone deacetylation is related to gene silencing due to the generation of heterochromatin. Both PTMs in histones and DNA methylation in regulatory regions are known to be altered in cancer cells. It has recently been shown that both the loss of acetylation of specific histones and the methylation marks can predict the evolution of the patient with human carcinomas.
Fig 3- Nucleosome structure and histone acetylation process
Anticancer molecules in diet-
Phytoestrogens are a group of substances derived from plants, which are structurally or functionally like estradiol. The main types of phytoestrogens are flavonoids, isoflavones, lignans, coumestans, and stilbenes. These molecules lower the risk of developing breast cancer in women who live in countries with high consumption of phytoestrogens, e.g., In Japan, high soy consumption (an abundant source of phytoestrogens) has been associated with a lower risk of breast cancer. Soflavones intake (soy consumption) is associated with a lower risk of developing lung cancer. Diets rich in lignans and isoflavones with a lower incidence of prostate and testicular cancer.
Antioxidants are substances that inhibit oxidation and avoid or remove oxidative stress. Cancer cells are characterized by increased oxidative stress, due to increased metabolism, and oxidative stress leading to genomic instability that can favor the carcinogenic process. Eg-Some phytochemicals through their antioxidant activity decrease UV-induced skin damage and they seem to be a good chemoprevention option to avoid skin cancer development
Conclusion-
This review shows with mechanistic approaches, how high-fat, high-carb, and intake of specific molecules (phytoestrogens, antioxidants), can modify the epigenome to modulate gene expression to promote or prevent cancer development. This is important not only for basic research and to understand the carcinogenic process but also for preventive medicine as well, since it provides the physicians and patients with more information that supports the importance of having a healthy lifestyle.
Reference-
Torres et.al., Obesity, the other pandemic: linking diet and carcinogenesis by epigenetic mechanisms
- By Debangana Banerjee
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