Introduction
The intricate relationship between diet, metabolism, and epigenetics is increasingly recognized as a critical factor in various diseases, including cancer and obesity. This article explores how dietary factors, particularly high-fat diets (HFDs), can influence metabolic pathways and epigenetic modifications, ultimately affecting disease progression. We delve into the role of specific metabolites, oncogenes, and epigenetic mechanisms in shaping the tumor microenvironment (TME) and adipocyte biology, providing a comprehensive overview of the current research landscape.
The Impact of High-Fat Diets on Cancer Progression
Obesity, driven by the widespread consumption of saturated fat- and sugar-rich foods, is a significant risk factor for numerous cancer types. Experimental and clinical studies have highlighted the potential of caloric restriction and weight management in reducing cancer advancement and improving treatment outcomes. However, the long-term sustainability of caloric restriction regimens remains a challenge, prompting the exploration of intermittent fasting-mimicking diets and precision nutrition approaches.
Metabolic Rewiring and Tumor Microenvironment
Metabolites like lactate, kynurenine, and arginine have emerged as key mediators in tumor-TME cross-talk, immune evasion, and therapy resistance. The question of whether systemic metabolic perturbations contribute to the intratumoral accumulation of metabolites that shape the TME and promote cancer progression is a critical area of investigation.
A study using the Hi-MYC prostate cancer mouse model demonstrated that an obesogenic HFD accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. This diet-induced glycolysis and lactate accumulation in tumors, leading to augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAMs) and FOXP3+ regulatory T cells. These changes were associated with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11.
In prostate cancer patients, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This research identifies how genetic drivers and systemic metabolism cooperate to hijack the TME and promote prostate cancer progression through oncometabolite accumulation.
Read also: Weight Loss Guide Andalusia, AL
The Role of c-MYC
The oncogene c-MYC (MYC) is frequently overexpressed and amplified in human malignancies, including prostate cancer. Understanding the druggable metabolic vulnerabilities driven by MYC is crucial, as it remains a challenging therapeutic target. The Hi-MYC transgenic model, which faithfully replicates the human disease, was used to investigate the mechanisms that promote late prostate cancer progression under prolonged exposure to obesogenic HFD.
Epigenetic Mechanisms in Adipocyte Biology
Adipocytes, key endocrine and secretory cells, play a crucial role in regulating energy metabolism. Dysfunctional adipocyte biology is a primary factor in the development of metabolic disorders associated with obesity and type 2 diabetes. Epigenetic mechanisms, particularly DNA methylation, have been extensively studied in the development and regulation of adipocytes. These mechanisms influence numerous biological processes in adipose tissue and adipocytes, including lipogenesis and lipid metabolism.
DNA Methylation and Demethylation
DNA methylation, typically occurring at cytosine-guanine dinucleotide (CpG) sites, mediates gene expression silencing in promoter regions. This process is catalyzed by a family of DNA methyltransferases (DNMTs), which transfer a methyl group from S-adenosylmethionine (SAM) to the fifth carbon of a cytosine residue, forming 5-methylcytosine (5mC). DNA methylation plays a crucial role in maintaining genomic stability, genomic imprinting, and chromatin structure.
The discovery of active DNA demethylation mechanisms mediated by ten-eleven translocation (TET) proteins has revealed that these mechanisms also profoundly influence various aspects of adipocyte biology. They regulate cellular differentiation and function by altering the methylation status of key genes involved in adipogenesis and metabolism.
Passive DNA Demethylation
Passive DNA demethylation was initially observed as a process associated with the failure to maintain DNA methylation and the reduced activity of DNMT enzymes. Studies have shown that a reduction in DNA methylation can facilitate cell differentiation.
Read also: Beef jerky: A high-protein option for shedding pounds?
Active DNA Demethylation
Active DNA demethylation involves protein-mediated hydroxymethylation by TET, deamidation by the AID/APOBEC family, and base excision repair (BER). TET proteins convert 5mC to 5-hydroxymethylcytosine (5hmC), an intermediate in the demethylation process.
The Role of DNMTs in Adipocyte Function
The human genome encodes five DNMTs: DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. DNMT1, DNMT3A, and DNMT3B are classical cytosine-5 DNMTs. DNMT1 preferentially targets hemimethylated DNA to maintain the methylation pattern during DNA replication, while DNMT3s primarily act on unmethylated DNA substrates, facilitating de novo methylation.
In lean murine adipocyte biology, silencing of DNMT1 accelerates adipogenic differentiation, while the expression of DNMT3A is significantly upregulated in the adipose tissue of obese mice.
DNMTs and Adipogenesis
The degree of methylation of specific genes, which depends on the enzymatic activity of DNMT, affects adipocytes, and overexpression of DNMT is a critical contributor to this regulatory process. DNMT3A overexpression stimulates the proliferation and inhibits the adipogenic differentiation of porcine intramuscular preadipocytes. Overexpression of DNMT1 and DNMT3A has opposite effects on lipogenesis in 3T3-L1 cells, promoting and inhibiting the process, respectively, during the pre- and late-stage differentiation phases.
Mice fed a HFD exhibit an increased number of hypermethylated regions and significant upregulation of DNMT3A expression, along with an increase in the methylation level of the leptin CpG promoter. HFD significantly altered the enzymatic activity and global DNA methylation status of DNMTs in the gonads of mice and increased the levels of DNMT1 and DNMT3A proteins in the ovaries and testes.
Read also: Inspiring Health Transformation
DNMTs and Obesity
DNMT1 is highly expressed in both visceral and subcutaneous adipose tissue of obese patients and exhibits a positive correlation with body mass index (BMI). DNMT1 and DNMT3A, highly expressed in individuals with obesity, contribute to the induction of obesity-associated inflammatory responses. Inflammatory factors promote DNMT1 activity in adults with obesity, suggesting a bidirectional interaction between DNMT enzymatic activity and the inflammatory response in the obese microenvironment.
DNMT1 and Lipid Metabolism
DNMT1 is hyperactivated in adipocytes of obese subjects and selectively methylates the promoter of adiponectin genes involved in lipid metabolism regulation, thereby inhibiting adiponectin expression. High glucose-induced lipid accumulation occurs via inducing DNMT1-mediated DNA hypermethylation of specific genes.
DNMT1 as a Therapeutic Target
DNMT1 is the most abundant DNA methylation modifier in adipose tissue, and adipocyte DNMT1 is required for the maintenance of the obese phenotype and systemic energy homeostasis. Adipocyte DNMT1 deficiency promotes lipid accumulation via promoter hypomethylation, exacerbates obesity-induced impairments in adipose tissue remodeling and energy metabolism, and induces hypertrophic expansion of adipocytes.