Metabolism and Epigenetic Regulation: Implications in Cancer

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