NAD
+ serves as a substrate for both sirtuin deacetylases and ADP-ribosyltransferases (ARTs). By adding ADP-ribose to histone proteins, these enzymes promote chromatin relaxation and increase the accessibility of transcription complexes to genomic DNA. As a result, the increase in NAD
+ induced by energy stress from CR leads to epigenetic remodeling and a rewiring of transcription through the deacetylation of histones by sirtuins at certain gene loci and the ADP-ribosylation of other loci, resulting in gene transcriptional reprogramming
[142][211].
α-Ketoglutarate is a crucial metabolic intermediate of the Krebs cycle that functions as a cofactor for various chromatin-modifying enzymes, such as histone demethylases (KDMs) and the TET family of enzymes, which are involved in DNA demethylation with TDG. The metabolic changes that occur due to calorie restriction and fasting result in an increase in α-Ketoglutarate, which alters the chromatin structure and DNA accessibility by regulating the activity of KDM and TETs
[142][211] (
Figure 3).
FAD
+, a crucial redox cofactor that plays a vital role in numerous metabolic reactions, operates as a coactivator of histone demethylases (JmjC). Reduced caloric intake, which is associated with caloric restriction and fasting, leads to increased levels of FAD
+, thereby promoting the demethylation of histones and ultimately resulting in the remodeling of the chromatin structure through the activation of histone demethylases
[142][211] (
Figure 3).
Acetyl-CoA, a product of the oxidative metabolism of glycolytic pyruvate, free fatty acids, branched-chain amino acids, and ketone bodies within the tricarboxylic acid cycle, plays a crucial role in epigenetic signaling. It serves as a vital cofactor for HAT acetyltransferase. During periods of fasting or caloric restriction, the scarcity of nutrients leads to an enhancement in autophagy and mitochondrial metabolism, which results in a decrease in metabolic cofactors, including acetyl coenzyme A. This essential compound is crucial for epigenetic remodeling and cell differentiation, leading to a decrease in histone acetylation and subsequent alteration in transcription.
6. Inflammation, Epigenetics, and Cancer
6.1. Inflammation in Tumor Onset and Progression
Chronic inflammation and tumor-induced inflammatory responses play a key role in promoting tumorigenesis and tumor progression by modulating the differentiation of immune and stromal cells towards immunosuppressive subtypes that support immune evasion and tumor growth
[4][143][4,216]. The release of proinflammatory cytokines, such as IL-1, IL-6, IL-8, and TNF-α, by immune, stromal, and tumor cells activates tumor proliferative and pro-survival signaling pathways, such as NF-κB and STAT3
[144][217]. Reactive oxygen species (ROS) produced by myeloid cells stimulate the tumor secretion of TNFα, which, in turn, drives the release of proinflammatory cytokines, creating a vicious loop of tumor-promoting factors
[145][218]. The production of ROS and oxidative nitrogen species, such as superoxide, hydroxyl radical, and peroxynitrite, by myeloid cells during inflammation in the tumor microenvironment causes DNA damage. This, in turn, activates the previously mentioned pro-inflammatory pathways, further fueling inflammation. This crosstalk between inflammation and DNA damage creates a feedback loop that promotes tumor progression
[146][219].
The inflammatory state within the tumor microenvironment could potentially be linked to the dysregulation of the inflammasome as a result of genetic mutations that accumulate within tumor cells. Gain-of-function mutations have been identified in NLRP1 and NLRP3 in various cancer types, including self-healing palmoplantar carcinomas, nodular melanoma, lung adenocarcinoma, small-cell lung cancer, bladder, gastric, and pancreatic cancer. AIM2 and GSDMD are overexpressed in non-squamous non-small-cell lung cancer, while GSDMD downregulation is associated with gastric cancer
[147][148][149][150][151][152][222,223,224,225,226,227].
Inflammasomes are activated in tumor cells, tumor-associated macrophages, tumor-associated fibroblasts, and bone-marrow-derived suppressive cells, resulting in the secretion of IL-1β and IL-18 in the TME
[153][154][155][156][228,229,230,231]. The release of IL-1β promotes the migration, invasion, and metastasis of melanoma and gastric cancer cells by increasing the expression of matrix metalloproteases MMP-2 and MMP-9
[157][232]. The activation of inflammasomes in myeloid cells, cancer-associated fibroblasts, and tumor-associated macrophages has been found to be positively correlated with the metastasis and poor survival rates of patients with breast and lung cancer
[156][158][159][160][231,233,234,235].
6.2. Epigenetic Alterations in Cancer
The onset and progression of cancer are closely associated with changes in the chromatin structure, resulting in distinct gene expression states and channel-specific phenotypic differentiation
[161][246]. Specific genetic mutations can alter the signaling pathway that drives cells to adopt specific genetic and epigenetic states, ultimately conferring a cancer-related phenotype
[162][247].
The process of epigenetic reprogramming in cancer is not solely attributable to mutations in oncogenes or tumor suppressor genes. Instead, it is influenced by alterations in genes that regulate epigenetic modifications. These changes in epigenetic regulation provide tumor cells with phenotypic plasticity and heterogeneity, allowing genetically identical cells to exhibit distinct phenotypes and temporarily modify their expression. These characteristics of tumor cells contribute to drug resistance, facilitate epithelial–mesenchymal transition (EMT), or enable immune evasion
[163][164][248,249].
Histone alterations in cancer. Abnormal patterns of histone and DNA modifications are prevalent in numerous tumor types. In human cancer cells, decreased global monoacetylation and trimethylation of histone H4 (H4K16ac and H4K20me3), altered methylation status of H3K9 and H3K27, and hypomethylation of repetitive DNA sequences are often observed
[165][250].
Somatic alterations in H3, particularly at amino acids K27, K36, and G34, promote the tumor initiation and progression of pediatric high-grade gliomas, including glioblastomas (GBMs)
[166][251]. These amino acid substitutions affect H3 methylation and acetylation, leading to an abnormal chromatin structure and gene expression.
Altered expression or mutation of epigenetic writers is frequently associated with several tumor types, including melanoma and breast, bladder, endometrial, renal cell, liver, and lung cancers, and it is often involved in tumor progression and metastasis
[167][252].
HATs are crucial in tumor development, as demonstrated by recurrent chromosomal translocations such as MLL-CBP and MOZ-TIF2, coding mutations (e.g., p300/CBP), and altered expression in solid and hematological malignancies
[168][169][253,254].
Somatic mutations in HDACs do not seem to be a significant factor in the development of cancer, yet the expression levels of various HDACs are altered in many types of malignancies. Cancer-related chimeric fusion proteins, such as PML-RARa, PLZF-RARa, and AML1-ETO, have been found to contribute to leukemogenesis by bringing HDACs to inappropriately silence genes, thereby promoting the development of leukemia
[170][256].
EZH2 is a component of the polycomb repressive complex 2 (PRC2), which is responsible for silencing gene transcription through the methylation of H3. Thus, both gain-of-function and loss-of-function mutations in EZH2 can result in chromatin remodeling, which in turn promotes tumor development by either repressing tumor suppressor genes or expressing oncogenes
[171][257]. In epithelioid sarcoma, EZH2 is constitutively active due to the inactivation of the SWI/SNF chromatin remodeling complex, which functions antagonistically to EZH2 by promoting active transcription through chromatin decompaction
[172][258]. The gain of function of EZH2 in mesothelioma is attributed to the mutation of BAP1, a deubiquitinating enzyme and component of the PR-DUB complex. The inactivation of BAP1 results in an increase in ubiquitinated H2AK119ub1, which then recruits the PRC2 complex and facilitates the methylation of H3K27me3 via EZH2. This leads to increased chromatin compaction and gene repression
[173][259].
Cytogenetics and next-generation sequencing analysis of diverse cancer genomes have consistently revealed frequent translocations and/or coding mutations in numerous KMT genes. In acute lymphoblastic leukemia, rearrangements of the histone lysine N-methyltransferase 2A (KMT2A) gene result in the production of aberrant fusion proteins that recruit DOT1-like histone lysine methyltransferase (DOT1L) to incorrect sites and methylates H3K79, causing the expression of oncogenes such as HOXA9 and MEIS1
[174][263].
Alterations in the expression of the lysine-specific histone demethylase LSD1 are frequently observed in various hematopoietic malignancies and solid tumors, including breast, lung, colorectal, and prostate cancers
[175][176][177][178][264,265,266,267].
Histone and DNA reader alterations in cancer. BET proteins have been implicated in a variety of diseases, including cancer, inflammation, and metabolic disorders. These proteins have been found to promote cancer development by altering gene expression in both tumor and TME cells
[179][270].
Multiple studies have reported alterations in the histone methylation lysine reader sequence or expression in both solid and hematological tumors
[180][273]. Nevertheless, the precise mechanisms that connect the disruption of methyl-lysine binding to chromatin to cancer development are not yet fully understood
[181][274].
DNA methyl binding proteins (MBDs) serve as epigenetic readers because they bind to methylated DNA and recruit enzymes that modify histones to coordinate chromatin processes. Mutations in MBD proteins have been identified in various human cancers and have been shown to be critical in the development of neoplasms
[182][183][184][185][275,276,277,278].
Alteration in chromatin remodeler in cancer. Chromatin remodelers are complexes that utilize ATP to shape the chromatin structure by moving, evicting, and exchanging histones. They act in response to the epigenetic modifications of chromatin and DNA generated by various epigenetic writers. There are four main families of chromatin remodelers: switch defective/sucrose non-fermenting (SWI/SNF), imitation switch (ISWI), nucleosome remodeling deacetylase/Mi-2/chromodomain helicase family (NuRD/Mi-2/CHD), and inositol requiring 80 (INO80) family
[186][279]. Chromatin remodeling complexes play a crucial role in granting access to condensed genomic DNA to regulatory transcription, thereby functioning in opposition to polycomb complexes, which repress the chromatin structure. Alterations and mutations in chromatin remodeler complexes can lead to an imbalance in the chromatin structure, which can promote tumor malignancy by disrupting the balance between cell self-renewal and differentiation genes and upregulating the expression of genes involved in cell cycle progression, cell motility, and nuclear hormone signaling
[187][280].
6.3. Inflammation-Induced Epigenetic Alterations in Tumor Immune Microenvironment
Chronic inflammation can lead to changes in the TME that trigger metabolic, genetic, and epigenetic alterations in both the tumor cells and the TME cells
[188][324]. Epigenetic changes can have a significant impact on gene expression and cell identity, potentially leading to the development of malignant and metastatic tumor cells. In addition to cancer cells, abnormal epigenetic modifications also take place in immune cells present in the tumor microenvironment. These modifications contribute to the creation of an immune-tolerant state by inducing T-cell exhaustion, enhancing the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) and decreasing tumor-associated antigens and T-cell co-stimulatory signals.
Epigenetic regulation of innate immune cells. The function of dendritic cells, which are essential for T-cell-mediated immunity, is altered in the TME. The epigenetic changes in the TME impede the maturation of dendritic cells, leading to immunotolerant phenotypes with a low expression of the major histocompatibility complex (MHC, a key component in antigen-presenting machinery) and co-stimulatory molecules
[189][326]. In pancreatic and colon cancer, FOXM1 overexpression, a transcription factor that suppresses DC maturation and function, is due to increased H3K79me2 methylation caused by dysregulated DOT1L methyltransferase activity
[190][327]. In the TME, KLF4 activation in dendritic cells inhibits their maturation by promoting IL-6 release, a dendritic maturation inhibitor, through hyperacetylation of histones in the IL-6 promoter
[191][192][328,329].
The microenvironment of tumors alters the function of macrophages, which are vital for both innate and adaptive immune responses, by promoting their polarization from a pro-inflammatory M1 phenotype with anti-tumor properties to an anti-inflammatory M2 phenotype with pro-tumor properties. Epigenetic mechanisms play a key role in regulating the polarization of M1/M2 macrophages through the control of their key transcription factors
[193][331]. The release of IL-4 in the TME promotes the expression of histone demethylase JMJD3 in macrophages, which then promotes the transcription of M2 gene markers (such as Arg1 and Retnla) by demethylating dimethyl and trimethyl H3K27 (H3K27me2/3) in their promoter regions
[194][141].
Myeloid-derived suppressor cells (MDSCs), including immature neutrophils and monocytes, are negative prognostic markers. They infiltrate the tumor microenvironment (TME) and create an immunosuppressive environment that permits tumor escape. The accumulation and immunosuppression functions of MDSCs in the TME rely on epigenetic processes. The immunosuppressive activity and proliferation of MDSCs depend on the production of immunosuppressive agents Arg1 and S100A8, which are regulated by the activation of STAT3. STAT3 activation relies on DNMT3a and DNMT3b, which suppress STAT3 expression by methylating its promoter region
[195][336]. The inhibitory effects of HDAC11 and HDAC6 on IL-10 (an activator of STAT3) resulted in the suppression of MDSC proliferation
[196][337].
The status of natural killer (NK) cells, which play a crucial role in the immune response against tumors by eliminating target cells and secreting cytokines, is often altered in tumors and is typically associated with reduced expression of activating receptors, such as NKG2D, NKp46, and KIR2DS, as well as an increase in the expression of inhibitory receptors, such as NKG2A and TIGIT. This is mainly due to aberrant DNA methylation and histone acetylation–methylation in the promoter regions of these receptors. In patients with hepatocellular carcinoma (HCC), it has been observed that the repression of NKG2D is linked to the hypermethylation and hypoacetylation of histone H3K9Ac in the NKG2D promoter region
[197][340].
Epigenetic regulation of adaptive immune cells. CD8
+ T cells are crucial in limiting tumor growth and preventing its progression. The differentiation of T-naive cells into T-effector cells, central memory cells, effector memory cells, and exhausted T cells depends on epigenetic mechanisms. However, the tumor and tumor microenvironment manipulate these mechanisms to render T cells dysfunctional and exhausted. T-cell exhaustion is characterized by an augmentation of transcriptional activity in genes associated with exhaustion, which is attributed to chromatin remodeling and relaxation. The expression of exhaustion markers, such as Tim-3, HMG box transcription factor Tox, and Tox2, is closely tied to the demethylation of their respective promoter regions
[198][343]. The lack of memory T cells in the tumor immune infiltration is due to specific demethylation at tissue-resident effector gene loci, such as CD39 and CD103
[199][344]. In pancreatic cancer, tumor-associated macrophages (TAMs) have the potential to impact the epigenetic landscape of tumor-infiltrating lymphocytes (TILs).
6.4. Nutrition and Cancer
Nutrition and diet have recently received considerable attention because of their potential impact on the development of neoplasms and as a complementary therapy to enhance the effectiveness of anti-tumor treatments. Despite numerous epidemiological studies assessing the effects of different dietary habits on health and cancer incidence, the results remain inconclusive. These studies found statistical differences among various dietary patterns, but the differences were small and difficult to reproduce
[200][201][202][353,354,355]. Confounding factors, such as socioeconomic status, age, physical activity, food quality, and cooking methods, may also influence the observed benefits of different dietary habits.
Nutrition can affect tumorigenesis in several ways, including modulating the immune system and inflammatory state; regulating endocrine factors, such as circulating insulin, insulin-like growth factor, leptin, and adiponectin
[203][356]; and influencing the gut microbiota
[204][357]. Although the mechanisms by which dietary macronutrients and micronutrients affect the inflammatory state are not yet fully understood, vitamin deficiencies, excessive food intake, and food deprivation have been shown to modulate the immune system and inflammatory processes
[205][358].
Overnutrition refers to the intake of excessive amounts of both macro- and micronutrients, which are then stored in the body’s tissues, especially adipose tissue. When there is no longer any space to store these excess nutrients, adipocytes swell and undergo changes that result in chronic inflammation, which can lead to noncommunicable diseases, such as diabetes mellitus, coronary artery disease, and stroke.
The overconsumption of food can lead to obesity, hyperlipidemia, and metabolic syndrome, which can cause chronic inflammation and predispose one to cancer
[206][359]. These conditions are associated with an increase in pro-inflammatory macrophage M1 and a decrease in anti-inflammatory M2 macrophages in adipose tissue, as well as an imbalance in the intestinal microbiota that leads to an accumulation of bacteria that produce procarcinogenic metabolites
[203][207][356,360]. Additionally, free fatty acids can activate Toll-like receptors, leading to the activation of the pro-inflammatory NF-κB and JNK1 pathways
[208][361]. Overnutrition also leads to an increase in acetyl-CoA, overactivation of mTOR, and reduction in the autophagic protein ATG7, all of which cooperate in blocking autophagy
[209][362]. The inhibition of autophagy can lead to the accumulation of damaged organelles that favor the aging process, activation of the NLRP3 inflammasome
[210][363], and accumulation of oncogenic P62
[211][364].
An unbalanced diet (excess or deficiency of macro- or micronutrients) may increase the risk of developing metabolic syndrome, which is characterized by elevated levels of various markers, such as C-reactive protein, glucose, IL-6, insulin, leptin, triglycerides, and low adiponectin. These changes can lead to inflammation and impair the immune system, increasing the risk of certain types of cancer.
Micronutrients, such as vitamin B6 and 25-hydroxyvitamin D, have been found to exhibit anti-tumor activity and to enhance anti-tumor immunosurveillance by preventing DNA damage and inflammation. High consumption of vitamin B6 and elevated plasma concentrations of its metabolite, pyridoxal-5′-phosphate (PLP), have been linked to a reduced risk of cancer, including gastrointestinal tumors
[212][370]. Increased levels of 25-hydroxyvitamin D in serum have also been associated with a decrease in pro-inflammatory markers and favorable prognosis in patients with breast cancer, prostate cancer, or colorectal cancer
[213][214][215][371,372,373].