Metabolic programs of individuals are key determinants for disease susceptibility and immune response. This book, edited by experts in the field, summarizes epigenetic signaling pathways that regulate metabolic programs associated with cancer and cancer-related secondary diseases.
The first part of the book highlights key metabolic pathways that are implicated in cancer and provides a comprehensive overview on the carbohydrate, protein, lipid, amino- and nucleic acid metabolic pathways that are deregulated in cancer. Special attention is paid to the altered tumor micro-environment that is influenced by the metabolic milieu. Furthermore, the fundamental relationship between the cellular metabolic environment and cell death-mediated autophagy is discussed.
The second part of the book covers our understanding of the fundamental epigenetic regulations that are implicated in controlling the metabolic programs in cancer cells. Many aspects of epigenetic regulation of non-coding RNAs as well as DNA/RNA methylation, which influencing metabolic homeostasis in cancer, are discussed in detail. Special emphasis is placed on the epigenetic regulation of the amino acid, glucose/carbohydrate metabolism and epigenetic regulation during hypoxia and its connection to cancer.
Last but not least, the third part of the book covers small molecule modulators of histone modifying enzymes, which can be used as therapeutic tools. The readers learn about the cross-talk between epigenetics and immunometabolims, as well as the epigenetic regulation of oncometabolites to combat cancer.
Given its scope, the book will appeal to a broad readership interested in epigenetic, cancer and metabolic research.
Author(s): Tapas Kumar Kundu, Chandrima Das
Series: Subcellular Biochemistry, 100
Publisher: Springer
Year: 2022
Language: English
Pages: 621
City: Cham
Foreword
Preface
Contents
Part I: Regulation of Key Metabolic Pathways in Cancer
Chapter 1: Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment
Introduction
Molecular Cues Influence Metabolic Phenotype in Different Cancers
Role of Hypoxia in Tumor Microenvironment
Metabolic Adaptation Due to Hypoxia in the Tumor microenvironment
Tumor Microenvironment Associated Cells
Role of Oncogenes and Tumor Suppressors in Metabolic Reprogramming in Cancer
Hormone-Regulated Metabolic Alterations
Carbohydrate Metabolism Plays a Key Role in Acquisition of Different Cancer Hallmarks
Proliferation
Bioenergetics
Macromolecule Biosynthesis
Redox Balance
Angiogenesis
Invasion and Metastasis
Epithelial to Mesenchymal Transition (EMT)
Intravasation and Circulating Tumor Cells
Extravasation and Colonization in the Metastatic Niche
Immune Escape
Escaping Cell Death and Acquiring Resistance
Epigenetic Regulation in Reprogramming Carbohydrate Metabolism in Cancer Cells and Tumor Microenvironment
Epigenetic Regulation of Metabolic Genes and Their Regulators Impacting Cancer Cells
DNA Methylation
Histone and Non-Histone Protein Modification
Non-Coding RNAs
Reliance of Tumor Microenvironment Sustenance on Epigenetic Regulation
Metabolites Dictating Epigenetic Landscape Impact Cancer Progression
Metabolites Serving as Coenzymes or Cofactors
SAM Regulates DNA and Histone Methylation
Acetyl Co-A Contributes to Histone Acetylation
NAD+ and α-KG Regulates Histone Deacetylation and Demethylation
Oncometabolites Regulating Metabolic Enzymes
Nuclear Metabolites Acting As a Source of Epigenetic Co-Factors
Therapeutic Strategies Targeting Epigenetics-Metabolism Crosstalk in Cancer
Epi-Drugs
Tumor Metabolite Inhibitors
Conclusion: Challenges and Future Perspectives
References
Chapter 2: Iron in Cancer Progression: Does BACH1 Promote Metastasis by Altering Iron Homeostasis?
Introduction
Iron Is High in Cancer Cells
The Regulation of Iron in Cancer Cells
Possible Roles for Iron in Cancer Cells
BACH1 Promotes Progression of Diverse Types of Cancers
Does BACH1 Regulate Iron in Cancer Cells?
Transcription Factor-Based Research into Cancer Cell Properties
References
Chapter 3: Regulation of Lipid Metabolism Under Stress and Its Role in Cancer
Introduction
Impact of Metabolic Stress on Lipid Metabolism in Cancer Cells
Effect of Hypoxia on Lipid Metabolism in Cancer Cells
Effect of Nutrient and Lipid Deprivation on Lipid Metabolism in Cancer Cells
Combinatorial Effect of Hypoxia and Nutrient Deprivation on Lipid Metabolism in Cancer Cells
Impact of Metabolic Stress on Lipidomic Profiles in Cancer Cells
Lipid/Lipidomic Profiles in Tumor Tissues and Tumor Spheroids
Targeting Lipid Metabolism for Cancer Therapy
Conclusions & Future Perspectives
References
Chapter 4: Role of the Histone Acetyl Transferase MOF and the Histone Deacetylase Sirtuins in Regulation of H4K16ac During DNA...
Introduction
MOF
SIRTUINS
Histone H4 Lysine 16 Acetylation (H4K16ac) in DNA Damage Repair
SIRTUINS Influence on Metabolic Regulation and Cancer
Connection Between Pre-Existing Histone Modifications and the DNA Damage Response and Repair in the Context of Cancer
Recruitment of Repair Proteins at DSBs Correlates with H4K16ac Status
MOF Suppresses DNA Replicative Stress by Facilitating Resolution of Stalled Replication Forks
Role of H4K16ac in Aging
Conclusion
References
Chapter 5: Autophagy in Cancer: A Metabolic Perspective
Introduction
Autophagy: A Mechanism of Cellular Defense
Epigenetic Regulation of Autophagy
Autophagy in Cancer
Autophagy and Cancer Therapy
Enhancement of Effectiveness of Anticancer Therapies by Inhibiting Autophagy
Enhancement of Effectiveness of Anticancer Therapies by Promoting Autophagy
Autophagy and Metabolism Crosstalk
Epigenetic Regulation of Metabolic Pathways and Its Implication in Autophagy
Conclusion/Future Perspectives
References
Part II: Epigenetic Regulation of Cellular Metabolic Pathways
Chapter 6: Long Non-coding RNAs, Lnc(ing) RNA Metabolism to Cancer Biology
Introduction
Origin and Development
Concepts and Facts
Functional Roles of LncRNA
Major Long Non-coding RNAs
Regulatory Roles
Association with RBPs
DNA Damage Response (DDR)
Maintenance of Chromatin States
Transcription
Post-transcription
Post-translational
LncRNA, Dual Regulators of Signalling Pathways in Cancer
LncRNAs Are Involved in Different Steps of the Signalling Cascade
Routes Through Which LncRNAs Regulate Signalling Pathways
Signalling Pathways Regulated by LncRNA: Building Blocks in Cancer Biology
LncRNA and Wnt Signalling
LncRNA and TGF-Beta Signalling
LncRNA and JAK-STAT Pathway
LncRNA and PI3/AKT Pathway
LncRNA and MAPK/ERK Signalling
LncRNA as Tumour Suppressors
GAS5
MT1JP
LET
MALAT1
MEG3
XIST
LncRNAs as Therapeutic Targets
Nucleic Acid Modulators of LncRNA
Small Molecule Modulators of LncRNA
Future Prospects
References
Chapter 7: Modulation of DNA/RNA Methylation Signaling Mediating Metabolic Homeostasis in Cancer
Introduction
Nucleic Acid Methylation
DNA Methylation
The Writers and Erasers of DNA Methylation
Cellular Function of DNA Methylation
RNA Methylation
The Writers and Erasers of m6A RNA Methylation
Cellular Function of m6A RNA Methylation
Metabolic Reprogramming of Cancer Cells
Nucleic Acid Methylation and Tumor Metabolism
DNA Methylation and Tumor Metabolism
Glucose Metabolism
Lipid Metabolism
Amino Acid Metabolism
Nucleotide Metabolism
RNA Methylation and Tumor Metabolism
Glucose Metabolism
Lipid Metabolism
Amino Acid and Nucleotide Metabolism
Crosstalk Between Methylome and Metabolome: A Target for Therapeutics
Summary and Future Perspectives
References
Chapter 8: Nutritional Epigenetics: How Metabolism Epigenetically Controls Cellular Physiology, Gene Expression and Disease
Introduction
Nutritional Requirements of the Cell: Amino Acids, Vitamins, and Minerals
Metabolism and Epigenetics
S-Adenosyl Methionine (SAM) and the Methyl Cycle: Methylation of Histones and DNA
Flavin Adenine Dinucleotide (FAD), 2-Oxoglutarate-Dependent Demethylases
Acetyl-CoA and Histone Acetylation
NAD+ and Histone Deacetylation
Metabolic Regulation of Disease Through Epigenetic Route
Fetal Reprogramming
Cardiovascular Disease (CVD)
Obesity and Type 2 Diabetes
Alzheimer´s Disease
Cancer
Conclusion
References
Chapter 9: Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer
Introduction
Role of Glucose Metabolism in Cancer Manifestation
Normal Cells: Glycolysis and TCA Cycle Are Balanced
Cancer Cells: Energy Production Shifts to Glycolysis-Warburg Effect
Deregulation of Glucose Metabolism in Cancer: Cause and Effects
Strategy of Cancer Cells Beyond Warburg Effect for Their Better Survival
Glycolysis and TCA Cycle Intermediates Help Cancer Cells for Biomass Production
Epigenetic Influences on Glucose Metabolism That Reprogram Cancer Cells Towards Survival
Metabolic Intermediates and Their Connection to Epigenetic Regulation
S-Adenosyl Methionine (SAM)
Acetyl CoA
Nicotinamide Adenine Dinucleotide (NAD+)
Tetrahydrofolate (THF)
Flavin Adenine Dinucleotide (FAD)
Other Metabolites for Non-canonical Histone Modifications
Acyl-coA
UDP-N-acetylglucosamine (UDP-GlcNAc)
Monoamines
Oncometabolites
Different Epigenetic Reader Domains and Their Functions
Methylation Readers
Lysine Methylation
Arginine Methylation
Acetylation Readers
Phosphorylation Readers
Ubiquitination Readers
Reader of H2A Ubiquitination
Reader of H2B Ubiquitination
Reader of H3 and H4 Ubiquitination
SUMOylation Readers
Mechanisms of Reprogramming the Metabolic Landscape Through Epigenetic Regulators
TRIM24
Mechanism of Action
Glucose Uptake
Glycolysis
TCA Cycle
UHRF1
Mechanism of Action
Gluconeogenesis
Glucose Uptake and Glycolysis
PHF20L1
Mechanism of Action
Glucose Uptake and Glycolysis
Hypoxia Response
ZMYND8
Mechanism of Action and Role in Hypoxia Response
TCF19
Mechanism of Action
Glucose Uptake
Glycolysis and OXPHOS
Gluconeogenesis
Methods to Determine the Metabolic Aberrations During Glucose Metabolism due to Alteration in Transcription Programs
Glucose Sensing
Indirect Glucose Uptake measurements:
3-O-methylglucose (3-MG)
2-deoxy-D-glucose (2-DG)
2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG)
Direct Glucose Uptake Measurements
3-Bromopyruvate
Oxidative Stress
ROS Assays
Direct Mode of ROS Measurements
Indirect Mode of ROS Measurements
RNS Assays
Glycolysis/TCA Cycle
Lactate Production Assay
Extracellular Acidification Rate Measurements
Gluconeogenesis Assays
Oxidative Phosphorylation
Mitochondrial Membrane Potential Measurements
Oxygen Consumption Rate Measurements
ATP Production Assay
Metabolomics-Based Mass Spectrometry Analysis
Analysis of Glucose Metabolic Enzymes
Enzyme Activity
Gene Expression
Role of Other Metabolic Pathways on Epigenetic Control of Glucose Metabolism
Amino Acid Metabolism
Fatty Acid Metabolism
Nucleotide Metabolism
Conclusion and Future Perspective
References
Chapter 10: Sirtuin 6 Is a Critical Epigenetic Regulator of Cancer
The Sirtuin Family
Sirtuin 6
Enzymatic Activity
Regulation of SIRT6
Transcriptional Regulation
Regulation by miRNAs
Posttranslational Regulation
Cellular and Molecular Functions
Histone Modifications
Metabolism
Glucose Homeostasis
Lipid Homeostasis
Genome Stability
DNA Repair
Telomere Maintenance
Stress Response and Aging
Sirtuin 6 in Cancer
SIRT6 as a Tumor Suppressor
SIRT6 as a Tumor Promoter
SIRT6 Modulators in Therapeutics
SIRT6 Activators
SIRT6 Inhibitors
Conclusion
References
Chapter 11: Epigenetic Regulation During Hypoxia and Its Implications in Cancer
Hypoxia
Hypoxia in Cancer
Epigenetic Pathways Involved in Driving Hypoxia-Induced Cellular Responses in Cancer
Chromatin Remodelers in Tumor Hypoxia
Histone Modifications in Tumor Hypoxia
Histone Methylation
Histone Acetylation
Other Histone Modifications
DNA Methylation and Hydroxymethylation in Tumor Hypoxia
RNA Methylation in Tumor Hypoxia
Noncoding RNAs
Micro-RNAs and Tumor Hypoxia
Long Noncoding RNAs and Tumor Hypoxia
Concluding Remarks
References
Part III: Epigenetic Regulation in Cancer
Chapter 12: Metabolic Regulation of Lysine Acetylation: Implications in Cancer
Introduction
Introduction to Lysine Acetylation: A Key Epigenetic Modification to Regulate Chromatin Structure and Gene Regulation
Reversible and Irreversible Lysine Acetylation
Writers, Erasers, and Readers of Lysine Acetylation
Impact of Lysine Acetylation on the Structure of Chromatin and Regulation of Gene Expression
Metabolic Regulation of Acetylation
Metabolic Regulation of Acetylation through Acetyl-CoA
Metabolic Regulation of Acetylation through NAD+
Metabolic Regulation of Acetylation through Other Metabolites
Metabolic Rewiring by Acetylation
Cellular and Organismal Variable Regulating Acetylation
Aging
Dietary Alterations
Hormones
Bacterial Infection
Acetylation and Cancer: A Metabolism View
Metabolic Rewiring of Acetyl-CoA Pathways in Cancer
Altered Glucose and Glutamine Metabolism
Altered Expression of Metabolic Enzymes
Altered Signaling
Role of Histone Acetylation in Cancer Progression
Metabolic Alterations of Acetyl-CoA Pathways and Its Implications in Oral Cancer
Metabolic Alterations of Acetyl-CoA Pathways in Oral Cancer
Acetylated Histone Marks Associated with Oral Cancer and Its Poor Prognosis
Acetylated Histone Marks as Biomarkers for Oral Cancer
Involvement of KATs in Imparting the Acetylation Signature Associated with Oral Cancer
Concluding Remarks and Future Perspectives
References
Chapter 13: The Cross-Talk between Epigenetic Gene Regulation and Signaling Pathways Regulates Cancer Pathogenesis
Introduction
Epigenetic Modifications Responsible for the Activation of Wnt Signaling Pathway
Epigenetic Silencing of Extracellular Wnt/β-Catenin Pathway Inhibitors SFRP Family
Dickkopf (DKK)
Epigenetic Silencing of Cytosolic Wnt/β-Catenin Pathway Inhibitors APC, AXIN2, and DACT Gene Family
Epigenetic Silencing of Nuclear Factors SOX7 and SOX17
Epigenetic Silencing of WNT Non-Transforming Ligands WNT5A, WNT7A, and WNT9A
Epigenetic Silencing of Epithelial Adhesion Molecules
Wnt Signaling Induces Epigenetic Alteration to Promote Cancer
Epigenetic Modifications Cause Activation of the Hedgehog (Hh) Signaling Pathway
Epigenetic Modifications of Ligands
Epigenetic Modifications of Hh Pathway Members PTCH1
SMO
HHIP
Epigenetic Modifications Cause Activation of PI3K/AKT Signaling Pathway
Epigenetic Silencing of Phosphatase and Tensin Homolog (PTEN)
Epigenetic Silencing of Rab Protein
Epigenetic Silencing of ADAMTS Protein
Epigenetic Silencing of HOXD10 Protein
PI3K/AKT Signaling Induces Epigenetic Alterations to Promote Cancer
AKT Directs Stabilization and Transcriptional Regulation of DNA-Methylating Enzymes
Epigenetic Regulation of Gene by AKT through Histone Modification
Histone Acetylation and Deacetylation
AKT Regulates Histone Methylation
H3K4 Trimethylation
H2A Ubiquitination by AKT Signaling
AKT-mTOR Signaling-Mediated Histone Acetylation in Cancer Progression
Ras Signaling Pathway Induces Epigenetic Alterations to Promote Cancer
Epigenetic Modification of JAK/STAT Signaling in Cancer Progression
Epigenetic Modification of NOTCH Signaling Pathway in Cancer
Epigenetics and Cancer Therapeutics
Application of Epigenetic Biomarkers for the Detection of Cancer at the Early Stage
Summary
References
Chapter 14: Epigenetic Regulation Towards Acquired Drug Resistance in Cancer
Introduction
DNA Methylation
Histone Modifications
Histone Acetylation
Histone Methylation
Other Histone Modifications: Phosphorylation, Ubiquitination, ADP-Ribosylation, and Biotinylation
Chromatin Remodeling Complexes
Non-Coding RNAs
Future Perspective
References
Chapter 15: Structural Basis of Targeted Imaging and Therapy in Cancer Explorations with the Epigenetic Drugs
Introduction
Cancer Exploration with Epigenetic Drugs
Classification of Epigenetic Cancer Drugs
DNA Methyltransferase Inhibitors
Histone Deacetylase Inhibitors (HDACIs)
Noncoding RNA-Based Therapeutics
Epigenetics: Cancer Targeting, Imaging, and Therapy
Monitoring Epigenetic Changes in Cancer by Various Imaging Techniques
Structural Aspects of Epigenetic Drugs/Small Molecules
Future Perspectives
References
Chapter 16: Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer
Introduction
Metabolic Deregulation in Cancer
Crosstalk Between Metabolomics and Epigenetics
Impact of Metabolic Changes on Enzymes that Catalyse Epigenetic Modifications
Role of Epigenetic Rewiring on Metabolic Gene Expression
DNA Methylation
Histone Modifications
RNA Epigenetics
Therapeutic Strategies to Target the Epigenetic-Metabolomic Crosstalk
Conclusion and Future Perspectives
References
Chapter 17: Modulation of DNA/RNA Methylation by Small-Molecule Modulators and Their Implications in Cancer
Introduction
DNA Methylation
DNA Methylation Profiles in Cancer
DNA Methylation: An Epigenetic Mark Storing Cellular Memory in DNA
The Role of TET and TDG Pathway in Cancer
Targeting DNMTs for Cancer Therapy
DNMT Inhibitors (DNMTi) in Cancer
Nucleoside Analogs as DNMT Inhibitors
Non-nucleoside-Derived DNMT Inhibitors
Antisense Oligonucleotides as DNMT Inhibitors
RNA Methylation and Its Types
N6-Methyl Adenosine (m6A)
N1-Methyladenosine (m1A)
2′-O-Methylation (2′-OMe/Nm)
5-Methylcytosine (m5C)
Writers, Erasers, and Readers for RNA Methylation
Writers as Methyltransferase
Eraser as a Demethylase
Readers
The Role of m6A Modification in Various Cancers
Small-Molecule Modulators for RNA Methylation
METTL14 Inhibition
FTO Inhibition
ALKBH5 and YTH Domain-Containing Proteins Inhibition
Conclusion and Future Perspectives
References
Chapter 18: Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer
Introduction
Macrophage Polarization in the TME
Key Metabolic Features of M1 and M2 Macrophages
Pentose Phosphate Pathway (PPP) in M1/M2 Macrophages
Tricarboxylic Acid (TCA) cycle in M1/M2 Macrophages
FAO/FAS in M1/M2 Macrophages
Role of Transcription Factors in TAM Polarization
Influence of the TME Signals on TAM Polarization
Epigenetic Regulation of Metabolism in Tumor-Associated Macrophages (TAMs)
DNA Methylation and Macrophage Polarization in the TME
Histone Modification and Macrophage Polarization in the TME
Metabolic Programming of Dendritic Cells (DCs) in the TME
Metabolic and Epigenetic Regulation of T-Cell Subsets in TME
Glucose Metabolism and Antitumor Effect of T Cells
Role of Lipid Metabolism in T Cells
Acetyl-CoA and Histone Acetylation in T-Cell Differentiation and Functioning
Role of TCA Intermediates in Epigenetic Modulation of T-Cell Differentiation
Glutamine
Connections Between α-Ketoglutarate and Histone Demethylases in T-Cell Functioning
2-Hydroxyglutarate (2-HG)
Methionine and Histone/DNA Methylation
Butyrate and Histone Deacetylases in Determination of Treg/Th17 Ratio in Cancer Progression
Myeloid-Derived Suppressor Cells (MDSCs)
Epigenetic and Metabolic Crosstalk in MDSC: Roles of AMPK and HIF1α Adenosine 5′-Monophosphate (AMP)-Activated Protein Kinase ...
Hypoxia-Inducible Factor 1-Alpha (HIF-1α)
Altered Epigenetic and Metabolic Features of NK Cells in the TME
Conclusion
References
Index
