Cancer Epigenetics

Preface
Contents
About the Editor
List of Contributors
Abbreviations
Part-I: Background
	Chapter 1: An Overview of Epigenetics Modifications in Normal and Cancer Cell
		1.1 Introduction
			1.1.1 DNA Methylation
			1.1.2 DNA Hydroxymethylation
			1.1.3 Histone Modifications
			1.1.4 Nucleosome Remodeling
			1.1.5 Non-coding RNAs
		1.2 Epigenetics in Normal Cell
			1.2.1 DNA Methylation in Normal Cell
			1.2.2 DNA Hydroxymethylation in Normal Cell
			1.2.3 Histone Modifications in Normal Cell
			1.2.4 Nucleosome Remodeling in Normal Cell
			1.2.5 Non-coding RNAs in Normal Cell
		1.3 Epigenetics in Cancer Cell
			1.3.1 DNA Methylation in Cancer Cell
			1.3.2 DNA Hydroxymethylation in Cancer Cell
			1.3.3 Histone Modifications in Cancer Cell
			1.3.4 Nucleosome Remodeling in Cancer Cell
			1.3.5 Non-coding RNAs in Cancer Cell
		1.4 Conclusion
		References
	Chapter 2: Epigenetic Enzymes and Their Mutations in Cancer
		2.1 Introduction
			2.1.1 DNA Methylation
				2.1.1.1 DNA Methyltransferase 1
				2.1.1.2 DNA Methyltransferase 3
				2.1.1.3 Mutations of DNA Methyltransferases
				2.1.1.4 Ten Eleven Translocation Proteins
				2.1.1.5 Mutations of Ten Eleven Translocation Proteins
			2.1.2 Histone Modifications
				2.1.2.1 Histone Acetyltransferases
				2.1.2.2 Mutations of Histone Acetyltransferases
				2.1.2.3 Histone Deacetylases
				2.1.2.4 Mutations of Histone Deacetylases
				2.1.2.5 Histone Methyltransferases
				2.1.2.6 Mutations of Histone Methyltransferases
				2.1.2.7 Histone Demethylases
				2.1.2.8 Mutations of Histone Demethylases
		2.2 Conclusion
		References
	Chapter 3: Introduction to Cancer Epigenetics
		3.1 Introduction
			3.1.1 History of Epigenetics
			3.1.2 Epigenetics and Epigenome
		3.2 Epigenetic Machinery
			3.2.1 DNA Methylation
				3.2.1.1 DNA Methyltransferases
				3.2.1.2 Methyl-CpG Recognition Proteins
				3.2.1.3 5-Hydroxymethyl Cytosine and TET Enzymes
				3.2.1.4 TET Proteins and DNA Demethylation
			3.2.2 Abnormal Epigenomic Reprogramming in Cancer
				3.2.2.1 Cancer-Specific DNA Methylation Alterations
				3.2.2.2 Global DNA Hypomethylation
					3.2.2.2.1 DNA Methyltransferases (DNMTs) and DNA Methylation
					3.2.2.2.2 Focal DNA Hypermethylation and Tumor Suppressor Genes
					3.2.2.2.3 Roles of DNA Methylation Aberrations in Cell Proliferation
					3.2.2.2.4 Role of DNA Methylation Changes in Evasion of Apoptosis
					3.2.2.2.5 Promotion of Genome Instability by DNA Methylation Alterations
			3.2.3 Histon Modifications in Cancer
				3.2.3.1 Histone Acetylation
				3.2.3.2 Histone Methylation
				3.2.3.3 Histone Ubiquitination
				3.2.3.4 Histone Phosphorylation
				3.2.3.5 Other Modifications
			3.2.4 Chromatin Remodelers
			3.2.5 miRNAs in Cancer
				3.2.5.1 miRNA Biogenesis and Functions
					3.2.5.1.1 Canonical miRNA Biogenesis
					3.2.5.1.2 Non-canonical miRNA Biogenesis
			3.2.6 The Role of miRNA in Cancer
				3.2.6.1 Proliferation and miRNAs in Cancer
				3.2.6.2 Apoptosis and miRNAs in Cancer
				3.2.6.3 Invasion, Metastasis, and miRNAs in Cancer
				3.2.6.4 Angiogenesis and miRNAs in Cancer
				3.2.6.5 Non-canonical Function of miRNA in Cancer
				3.2.6.6 Deregulation of miRNA Expression in Cancer
			3.2.7 Circulating miRNA in Cancer
			3.2.8 miRNA-based Biomarkers in Cancer
			3.2.9 miRNA-Based Therapies in Cancer
				3.2.9.1 Approaches for miRNA Therapeutic Delivery
		3.3 Conclusion
		References
Part II: Cancer Specific Epigenetic Alterations
	Chapter 4: Epigenetics in the Diagnosis, Prognosis, and Therapy of Cancer
		4.1 Epigenetics and Cancer
			4.1.1 Histone Modification
			4.1.2 DNA Methylation
			4.1.3 Noncoding RNAs
			4.1.4 Chromatin Remodeling
		4.2 Epigenetics in Cancer Diagnosis
			4.2.1 DNA Methylation as a Biomarker of Cancer Diagnosis
			4.2.2 Histone Modification as a Biomarker of Cancer Diagnosis
			4.2.3 Non-encoding RNAs as Biomarkers of Cancer Diagnosis
			4.2.4 Imprinted Genes as Biomarkers of Cancer Diagnosis
		4.3 Epigenetic in Cancer Prognosis
			4.3.1 DNA Methylation in Cancer Prognosis
			4.3.2 Histone Modifications in Cancer Prognosis
			4.3.3 Histone Variants and Chromatin Remodeling in Cancer Prognosis
			4.3.4 Noncoding RNAs in Cancer Prognosis
		4.4 Epigenetics in Cancer Therapy
			4.4.1 Targeting DNA Methylation-Related Enzymes in Cancer Treatment
			4.4.2 Targeting Histone Acetylation-Related Enzymes in Cancer Treatment
			4.4.3 Targeting Other Epigenetic Biomarkers in Cancer Treatment
		4.5 Conclusions and Perspectives
		References
	Chapter 5: Clinical Studies and Epi-Drugs in Various Cancer Types
		5.1 Introduction
		5.2 Epigenetic Studies Regarding the Most Common Solid Tumor Types
			5.2.1 Lung Cancer
			5.2.2 Breast Cancer
			5.2.3 Colorectal Cancer
			5.2.4 Prostate Cancer
			5.2.5 Cutaneous Melanoma
			5.2.6 Epigenetic Studies Regarding the Most Common Hematological Malignancies
				5.2.6.1 Myeloid Leukemias
				5.2.6.2 Lymphoid Leukemias
				5.2.6.3 Lymphomas
		5.3 Conclusion
		References
	Chapter 6: Epigenetic Regulation in Breast Cancer Tumor Microenvironment
		6.1 Introduction
		6.2 Tumor Microenvironment in Breast Cancer
			6.2.1 Tumor-Associated Macrophages (TAMs)
			6.2.2 Helper T Cells and Cytotoxic T Cells
			6.2.3 Natural Killer Cells (NK Cells)
			6.2.4 Dendritic Cells (DCs)
			6.2.5 Myeloid-Derived Suppressor Cells (MDSCs)
			6.2.6 Cancer-Associated Fibroblasts (CAFs)
			6.2.7 Endothelial Cells
			6.2.8 Cytokines and Chemokines
		6.3 Epigenetic Modifications in Breast Cancer Tumor Microenvironment
			6.3.1 DNA Methylation
			6.3.2 Histone Modifications
			6.3.3 NcRNA-mediated Gene Silencing
		6.4 Epigenetic Modulators in the Tumor Microenvironment of Breast Cancer
		6.5 Conclusion
		References
	Chapter 7: The Epigenetics of Brain Tumors: Fundamental Aspects of Epigenetics in Glioma
		7.1 Introduction
		7.2 Overview of Epigenetic Mechanisms
			7.2.1 DNA Methylation
				7.2.1.1 DNA Demethylation and Hypermethylated Phenotype
			7.2.2 Posttranslational Modifications of Histones
			7.2.3 Noncoding RNAs
		7.3 Epigenetic Changes in Gliomas
			7.3.1 Glioma CpG Island Methylator Phenotype (G-CIMP)
			7.3.2 IDH1 Mutations and Relationship to Epigenetic Changes in Gliomas
				7.3.2.1 IDH1 and IDH2 Genes
				7.3.2.2 Classifying Marker 1p/19q Codeletion
				7.3.2.3 MGMT Promoter Methylation
				7.3.2.4 IDHs, G-CIMP Status, and MGMT Promoter Methylation Relations
		7.4 Epigenetic Biomarkers Related with Chromatin Modifications
			7.4.1 CTCF (CCCTC-Binding Factor)
			7.4.2 Nuclear Alpha-Thalassemia/Mental Retardation X-Linked Syndrome (ATRX) Gene
		7.5 Histone Modifications
			7.5.1 Histone Acetylation
			7.5.2 Histone Methylation and Pediatric Gliomas
		7.6 Noncoding RNA and Glial Tumors
		7.7 Conclusion
		References
	Chapter 8: Epigenetic Alterations in Pancreatic Cancer
		8.1 Introduction
		8.2 Genetic Alterations in Pancreatic Cancer
		8.3 Epigenetic Events in Pancreatic Cancer
			8.3.1 DNA Methylation
			8.3.2 Histone Modification
				8.3.2.1 Lysine Residue-Specific Methylation
				8.3.2.2 Lysine-Specific Demethylation
				8.3.2.3 Arginine-Specific Methylation
		8.4 Conclusion
		References
	Chapter 9: Current Preclinical Applications of Pharmaco-Epigenetics in Cardiovascular Diseases
		9.1 Cardiovascular Diseases: From Ischemic Injuries to Heart Repair
		9.2 The Impact of Epigenetics on Cardiovascular Activity
		9.3 Epigenetic Machinery in Cardiovascular Diseases
			9.3.1 DNA Methylation Role in CVD
			9.3.2 Histone Modifications in CVD
			9.3.3 Histone Deacetylases in CVD
			9.3.4 Histone Methylation in CVD
			9.3.5 Noncoding RNAS in CVD
		9.4 Epigenetic Dysregulation and Cardiovascular Disease Susceptibility.
		9.5 Epigenetic Biomarkers in Cardiovascular Diseases
			9.5.1 Epigenetic Biomarkers in MI
			9.5.2 Epigenetic Biomarkers in HF
			9.5.3 Epi-Biomarkers in Arrhythmia
		9.6 Preclinical Evidence of Pharmaco-Epigenetic Role in Cardiovascular Diseases
			9.6.1 Histone Modifications
			9.6.2 DNA Methylation
			9.6.3 Noncoding RNA
		9.7 Epigenetic-Based Therapies in Cardiovascular Diseases and Future Perspectives
		9.8 Potential Effects of Existing Drugs on Epigenetic Modulators in Cardiovascular Disease
		References
	Chapter 10: Epigenetic Alterations in Colorectal Cancer
		10.1 Introduction
		10.2 Aberrant DNA Methylation
			10.2.1 DNA Methylation Alterations in Colorectal Cancer (CRC)
				10.2.1.1 Hypermethylation
				10.2.1.2 Hypomethylation
			10.2.2 DNA Methylation and the Pathogenesis of Colorectal Cancer: ``Traditional´´ and ``Serrated´´ Polyp Pathways
			10.2.3 Clinical Applications of DNA methylation in Colorectal Cancer
				10.2.3.1 Stool-Based Biomarkers
				10.2.3.2 Blood-Based Biomarkers
				10.2.3.3 Epigenetic Prognostic Biomarkers
				10.2.3.4 Epigenetic Predictive Biomarkers for Response to Treatment
				10.2.3.5 Colorectal Cancer and ``Field Cancerization´´
			10.2.4 Chromatin Alterations and Histone Modifications
				10.2.4.1 Overview of Histone Biology
				10.2.4.2 Histone Modification Alterations in Colorectal Cancer and Potential for Clinical Applications
			10.2.5 microRNA and Colorectal Cancer
				10.2.5.1 Overview of miRNA Biology
				10.2.5.2 Dysregulation of miRNA Expression in ``Traditional´´ and ``Serrated´´ Pathways
			10.2.6 miRNAs as Diagnostic Biomarkers in Colorectal Cancer
				10.2.6.1 Blood-Based Biomarkers
				10.2.6.2 Stool-Based Biomarkers
			10.2.7 miRNAs as Prognostic Biomarkers in Colorectal Cancer
			10.2.8 Predictive Biomarkers for Response to Treatment in Colorectal Cancer
		10.3 Conclusion and Future Directions
		References
	Chapter 11: Epigenetic Alterations in Hematologic Malignancies
		11.1 Introduction
		11.2 Hematological Cancers with Abnormal DNA Methylation
			11.2.1 Inhibitors of DNA-Methyltransferase
			11.2.2 The TET Enzymes and Hydroxymethylation of DNA
		11.3 The Relationship Between Metabolism and Epigenetics and -Ketoglutarate
		11.4 Histone Modification
			11.4.1 Acetylation
			11.4.2 Inhibitors of Histone Deacetylase
		11.5 Noncoding RNAs
		11.6 Conclusion
		References