Targeting Lysine Demethylases in Cancer and Other Human Diseases (Advances in Experimental Medicine and Biology, 1433)

Preface
Contents
1 Lysine Demethylation in Pathogenesis
	Abstract
	1.1	Epigenetic Regulation and Human Health
	1.2	Histone and Histone Methylation
	1.3	Histone Demethylases
	1.4	Functions of Histone Demethylases
	1.5	KDMs and Human Diseases
	1.6	Targeting KDMs in Human Diseases
	1.7	Conclusion
	References
2 Targeting the LSD1/KDM1 Family of Lysine Demethylases in Cancer and Other Human Diseases
	Abstract
	2.1	Introduction: Discovery of the First Histone Demethylase, LSD1/KDM1A
	2.2	Structure, Mechanism, and Biological Function of the KDM1 Family
		2.2.1	Domain Organization and Structural Features of the KDM1 Family
		2.2.2	Enzymatic Mechanism of Action of the KDM1 Family
		2.2.3	KDM1 Substrates and Protein Interactions
			2.2.3.1 Histone Substrates
			2.2.3.2 Non-histone Substrates
		2.2.4	Functional Interactions of KDM1 Demethylases with Other Biomolecules in Different Cellular Complexes
	2.3	Involvement of the KDM1 Family in Different Biological Processes
		2.3.1	Role of KDM1A in Stem Cells
		2.3.2	Role of KDM1A in Hematopoietic Cell Differentiation
		2.3.3	Role of KDM1A in Maternal Trophoblast Stem Cell Differentiation
		2.3.4	Role of KDM1A in Adipose Differentiation and Metabolism
		2.3.5	Role of KDM1A in Skeletal Muscle Differentiation
		2.3.6	Role of KDM1A in Neurogenesis
		2.3.7	Emerging Biological Roles for KDM1B
	2.4	KDM1A and Cancer Development
		2.4.1	AR and Prostate Cancer
		2.4.2	Estrogen Receptor (ER) and Breast Cancer
		2.4.3	Acute Myeloid Leukemia (AML)
		2.4.4	Small Cell Lung Cancer (SCLC) and Non-small Cell Lung Cancer (NSCLC)
		2.4.5	Other Tumors
		2.4.6	Emerging Role of KDM1 in Cancer Cell Evasion of Immune Surveillance
	2.5	KDM1 Demethylase as a Target in Cancer Therapy
	2.6	Classes of KDM1 Inhibitors
		2.6.1	MAO Inhibitors and Derivatives
		2.6.2	Peptide-Based KDM1A Inhibitors
		2.6.3	Polyamine-Based KDM1A Inhibitors
		2.6.4	Natural Products as KDM1A Inhibitors
		2.6.5	Multifunctional Inhibitors
		2.6.6	Other KDM1A Inhibitors
		2.6.7	KDM1A Inhibitors in Clinical Trials
	2.7	Conclusions and Future Perspectives
	References
3 Biological Functions of the KDM2 Family of Histone Demethylases
	Abstract
	3.1	Introduction
	3.2	Structure and Function of KDM2 Demethylases
	3.3	KDM2 Demethylases in Polycomb-Mediated Gene Silencing
	3.4	Non-histone Targets of KDM2 Demethylases
	3.5	Role of KDM2 Demethylases in Replicative Senescence, Stem Cell Biology and Somatic Cell Reprogramming
	3.6	KDM2 Demethylases in Normal Development and Tissue Homeostasis
	3.7	KDM2 Demethylases in Cancer
	3.8	Targeting KDM2 Demethylases with Small Molecule Inhibitors
	References
4 Histone Demethylase KDM3 (JMJD1) in Transcriptional Regulation and Cancer Progression
	Abstract
	4.1	Introduction
	4.2	Discovery of KDM3A as an H3K9me1/2 Demethylase
	4.3	KDM3 in the Demethylation of Non-histone Proteins
	4.4	Physiological Functions of KDM3A
		4.4.1	Spermatogenesis
		4.4.2	Metabolism
		4.4.3	Sex Determination
		4.4.4	Stem Cell Pluripotency
	4.5	Roles of KDM3A in Gene Regulation and Cancer
		4.5.1	KDM3A is a Coactivator for the Androgen Receptor and Estrogen Receptor
		4.5.2	KDM3A Acts as a Coactivator for Other Transcription Factors
		4.5.3	KDM3A Regulates c-Myc Expression
		4.5.4	KDM3A Regulates Expression of Other Transcription Factors
		4.5.5	KDM3A in Hypoxia Response
		4.5.6	KDM3A in Anoikis
	4.6	Roles of KDM3B and KDM3C in Cancer
	4.7	Regulation of KDM3A by Posttranslational Modifications
	4.8	Regulation of KDM3A by MicroRNAs
	4.9	Conclusion and Future Perspective
	References
5 KDM4 Demethylases: Structure, Function, and Inhibitors
	Abstract
	5.1	Introduction
	5.2	Structural Domain and Biochemistry of KDM4 Demethylases
	5.3	Expression and Physiological Roles of KDM4 Demethylases
	5.4	Regulatory Mechanisms of KDM4 Expression and Activation
	5.5	Alterations and Roles of the KDM4 Demethylases in Cancer Development
		5.5.1	KDM4A
		5.5.2	KDM4B
		5.5.3	KDM4C
		5.5.4	KDM4D
	5.6	Targeting KDM4 Demethylases with Small-Molecule Inhibitors
		5.6.1	Cofactor Mimics and Disruptors
		5.6.2	Histone Substrate Competitive Inhibitors
	5.7	Conclusions
	References
6 KDM5 Lysine Demethylases in Pathogenesis, from Basic Science Discovery to the Clinic
	Abstract
	6.1	Introduction
	6.2	Structure and Activity of KDM5 Demethylases
	6.3	KDM5 and Gene Regulation
		6.3.1	Transcriptional Regulation
		6.3.2	Other Gene Regulation Processes
	6.4	Biological Function of KDM5
		6.4.1	KDM5 Gene Expression and Knockout Animals
		6.4.2	Pluripotency and Differentiation
		6.4.3	Tissue-Specific Development
		6.4.4	Immune Regulation
		6.4.5	Aging
	6.5	KDM5 in Cancer
		6.5.1	KDM5A
		6.5.2	KDM5B
		6.5.3	KDM5C
		6.5.4	KDM5D
		6.5.5	KDM5 and Drug Resistance
	6.6	KDM5 Inhibitors
	6.7	Summary
	References
7 Context-Dependent Functions of KDM6 Lysine Demethylases in Physiology and Disease
	Abstract
	7.1	Introduction
		7.1.1	Epigenetics and Histone Modifications
		7.1.2	The Myth of Irreversibility for Histone Methylation
		7.1.3	Discovery of Lysine 27 Histone Demethylases
	7.2	Demethylase-Dependent Biochemical and Physiological Roles of JMJD3 and UTX
		7.2.1	Demethylase-Independent Molecular Functions for H3K27me3 Histone Demethylases
	7.3	Modeling JMJD3 and UTX Activity In Vivo
		7.3.1	JMJD3 and UTX: Friends or Foes?
			7.3.1.1 T Cell Development: JMJD3 and UTX Collaborative Activities
			7.3.1.2 Stem Cell Reprogramming and Differentiation: Contrasting Roles for UTX and JMJD3
	7.4	Roles of Lysine 27 Demethylases in Disease
		7.4.1	Cancer Studies Showed a Substantially Diverse Repertoire of JMJD3 Functions
		7.4.2	The Talented Mr. JMJD3: The Role of JMJD3 in Neurogenesis and Brain Tumors
		7.4.3	UTX Mainly Acts as a Tumor Suppressor in Cancer
		7.4.4	JMJD3 and UTX: Two Demethylases, Several Combinations
		7.4.5	Context-Dependent Oncogenic Roles for UTX in Cancer: Leukemia and Solid Tumors
		7.4.6	Contrasting Roles for JMJD3 and UTX in T-ALL
	7.5	Inhibiting Histone Demethylases
		7.5.1	Enzymatic Function of Lysine Demethylases
		7.5.2	Inhibition of JMJD3 and UTX: Challenges and Progress
			7.5.2.1 Crystal Structure Analyses
			7.5.2.2 Inhibitors for Lysine 27 Demethylases
	7.6	Conclusions and Future Perspective
	References
8 KDM7 Demethylases: Regulation, Function and Therapeutic Targeting
	Abstract
	8.1	Members of the KDM7 Family: Their Demethylation Activities in Transcriptional Regulation
		8.1.1	The Demethylation Activities of PHF8 and Their Roles in Transcriptional Regulation
		8.1.2	Dual Demethylation Activities of KDM7A on H3K9me2 and H3K27me2
		8.1.3	The Induced Demethylation Activity of PHF2
	8.2	Roles of KDM7 Family Members in Development
		8.2.1	Development of Craniofacial Structure, Bones and Neurons
		8.2.2	Adipogenesis
		8.2.3	Development of Other Systems
	8.3	Roles of KDM7 Family Members in Cancer
		8.3.1	PHF8: Oncogenic Functions in Various Cancers
		8.3.2	KDM7A: A Tumor Suppressor?
		8.3.3	PHF2: Dual Roles in Cancer?
	8.4	Regulation of KDM7 Family Members
		8.4.1	Transcriptional Regulation
		8.4.2	Post-transcriptional Regulation
		8.4.3	Post-translational Regulation
	8.5	Targeting KDM7 Family Members in Cancer Therapies
	8.6	Perspectives
	References