The Killer's Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer

Abstract

Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches.

Keywords: DNA repair; cancer; epigenetic; inflammation; nutrition.

Figure 1

Inflammatory signaling pathways. cGAS is activated upon the recognition of cytosolic double-stranded DNA derived from viruses, bacteria, dead cells, or mislocalized endogenous DNA. Activated cGAS synthesizes 2′-3′ cyclic GMP-AMP (cGAMP), which promotes the translocation of stimulator of interferon gene (STING) from the endoplasmic reticulum (ER) membrane to the ER-Golgi intermediate and Golgi compartments. STING forms a complex with TANK-binding kinase 1 (TBK1), which recruits and activates interferon regulatory factor 3 (IRF3), leading to the transcription of genes encoding inflammatory cytokines such as interleukin 6 (IL-6), interleukin 12 (IL-12), and interferons (IFNs). RIG-I-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5), laboratory of genetics and physiology 2 (LGP2), and retinoic acid-inducible gene I (RIG-I), interact with viral double-stranded RNA (dsRNA) and 5′-triphosphate single-stranded RNA and bind to mitochondrial antiviral-signaling protein (MAVS), which activates IRF3 and 7 via TBK1 and IκB Kinase ε (IKKε). Phospho-IRF3 and phospho-IRF7 transcribe genes encoding IFNs and immunoregulatory genes. Toll-like receptors (TLRs) recruit adapter protein myeloid differentiation primary response 88 (MyD88) and TIR domain-containing adaptor protein (TRIF) upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) on the plasma membrane or in endosomes (not depicted in the caption). MyD88 and TRIF initiate a signaling cascade resulting in the activation of NLR inflammasome, nuclear factor kappa B (NF-κB), interferon regulatory factors (IRFs), or mitogen-activated protein kinases (MAPK) which result in transcription of proinflammatory cytokines and inflammasome component NLR family pyrin domain containing 3 (NLRP3). The stimulation of NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) primes the assembly of the inflammasome complex, which triggers caspase-1 mediated cleavage of pro-IL-1β and pro-IL-18 and Gasdermin D precursor, which forms a pore on the plasma membrane through IL-1β and IL-18 being released into the extracellular matrix. C-type lectin receptors (CLRs) play a crucial role in modulating Toll-like receptor (TLR) signaling. They achieve this through two distinct mechanisms: either by activating NF-kB via RAS-RAF1 dependent signaling, or by recruiting spleen tyrosine kinase (SYK) to the phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) of the paired signaling adaptor Fc receptor γ-chain (FcRγ). The recruitment of SYK to FcRγ inhibits the recruitment of MYD88, thereby reducing the production of TLR-induced cytokines (created with BioRender.com).

Figure 2

Key epigenetic mechanisms controlling cancer, inflammation, and nutrition. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs play a significant role in regulating the expression of genes associated with inflammation, cancer, and nutrient conditions. In cancer cells, alterations in metabolic pathways occur during tumorigenesis and progression. These metabolic changes are often closely linked to epigenetic modifications and are influenced by inflammation and nutrition. The balance of histone and DNA modifications is crucial for proper regulation. The level of histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). High levels of histone acetylation promote gene transcription by opening chromatin and facilitating the recruitment of transcription factors and the transcriptional machinery. Histone methyltransferase (KMT) enzymes possess the ability to monomethylate, dimethylate, or trimethylate histone tail lysine and arginine residues, which can subsequently be removed by histone demethylase (KDM) enzymes. The methylation of histones at specific lysine and arginine residues is critical for determining the structure of chromatin and the recruitment of transcriptional repressors or activators. The enzyme DNA methyltransferases (DNMTs) catalyze the DNA methylation of the 5-carbon of cytosine, resulting in the formation of 5-methylcytosine. On the other hand, the removal of the methyl group is carried out by the activity of the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes, which progressively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine. Thymine-DNA glycosylase (TDG) removes 5-formylcytosine and 5-carboxylcytosine, which are then replaced by cytosine. In human cancers, CpG methylation promotes transcriptional silencing and malignant transformation, while hypomethylation of the transposable element DNA leads to genomic instability and an inflammatory response. Long non-coding RNAs (lncRNAs) can interact with chromatin modifiers and recruit them to the promoters of target genes, where they can activate or suppress transcription. Additionally, lncRNAs can sequester chromatin modifiers away from the promoters of target genes and regulate transcription. Mature microRNAs (miRNAs) are incorporated into a large protein complex known as RNA-induced silencing complex (RISC). This complex either cleaves messenger RNA (mRNA) or induces translational repression by binding to the 3′ untranslated region (UTR) of the target mRNA. Alternatively, it can induce translational activation if it binds to open reading frame (ORF) sequences or the 5′-UTR. miRNAs can modulate gene transcription through direct binding or by altering methylation patterns at the promoter level of the target gene (created with BioRender.com).

Figure 3

Nutrient-induced metabolic and epigenetic changes. The regulation of cellular genetics and epigenetics by calorie restriction (CR) and periodic fasting (PF) is achieved through the modulation of metabolism and hormonal systems. By reducing the levels of tumor growth-promoting nutrients and factors, including glucose, insulin like growth factor 1 (IGF1), and insulin, these interventions inhibit the IGF1-PI3K-AKT-mTOR and protein kinase A (PKA) signaling pathways, activate AMP-activated protein kinase (AMPK), and lead to the activation of stress-resistance genes that protect against the onset of age-related diseases. The decreased availability of glucose results in the liberation of amino acids and fatty acids from muscle and adipose tissue, respectively. Amino acids are utilized for glucose production through the process of gluconeogenesis, while fatty acids in the liver are converted into ketone bodies, which serve as the primary source of energy during periods of nutritional restriction. These metabolic adjustments shift cellular metabolism from glycolysis to oxidative phosphorylation. These modifications result in the formation of acetyl-CoA, which serves as an acetyl group donor for histone acetyltransferase (HAT)-dependent acetylation of nucleosomal histones. The elevation of NAD+ resulting from energy scarcity or the augmentation of de novo synthesis from amino acids, such as tryptophan, triggers the activation of histone deacetylase (HDAC) sirtuins (SIRTs). These sirtuins subsequently deacetylate histone H3, which in turn modulates the expression of metabolic genes and pathways, including glycolysis, gluconeogenesis, mitochondrial respiration, fatty acid oxidation, and lipogenesis. α-ketoglutarate (α-KG), which is produced from glutamine and participates in the TCA cycle, functions as a cofactor for the catalytic activity of lysine demethylase (JMJc) and ten-eleven translocation (TETs) enzymes, which play a role in DNA demethylation. Variations in glutamine and glucosamine glucose levels have an impact on the biosynthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and, consequently, the O-GlcNAcylation (OGT) of histones and proteins, which subsequently influence epigenetic reshaping. FAD+ levels generated by the KREBs cycle modulate the activity of LSD1 histone demethylases (created with BioRender.com).