This book focuses on histone mutations, especially those mutations closely related to cancer. Genetic mutations and epigenetic alterations contribute to the development of a variety of cancers: recent genetic studies have identified e.g. H3K27M and H3G34R/V mutation in over 75% of DIPG cases, H3.3K36M mutation in more than 90% of chondroblastoma cases, and H3G34W/L mutation in over 90% of giant cell tumors of bone. Given the high incidence and tumorigenesis effects of histone H3 mutations, they are also referred to as oncohistones. This book highlights the advances made in the area over the past 10 years, and offers a state-of-the-art summary of epigenetic alternation, gene expression, protein structure, drug discovery, immunotherapy, and mouse modeling of histone H3 mutations in various tumors. Chiefly intended to provide researchers and graduate students with an overall picture of these mutations, it will also be of interest to researchers in basic oncology, clinical oncology, and epigenetics, as well as academics and clinical oncology practitioners.
Author(s): Dong Fang; Junhong Han
Series: Advances in Experimental Medicine and Biology, 1283
Publisher: Springer Singapore
Year: 2020
Language: English
Pages: 102
City: Singapore
Acknowledgement
Contents
Chapter 1: Overview of Histone Modification
1.1 Histone Methylation
1.1.1 H3K4 Methylation
1.1.2 H3K9 Methylation
1.1.3 H3K27 Methylation
1.1.4 H3K36 Methylation
1.1.5 H3K79 Methylation
1.1.6 H4K20 Methylation
1.2 Histone Acetylation
1.3 Histone Phosphorylation
1.4 Chromatin Remodeler
1.5 Non-coding RNA
References
Chapter 2: The Histone H3 Family and Its Deposition Pathways
2.1 Introduction
2.1.1 Chromatin
2.1.2 Histones
2.1.3 Replicative Histones and Histone Variants
2.2 The Histone H3 Family
2.2.1 Replicative H3.1 and H3.2
2.2.2 H3.3 Variant
2.2.3 CenH3CENP-A Variant
2.3 Histone H3-H4 Chaperones
2.3.1 Histone Chaperone Definition
2.3.2 Dedicated H3-H4 Chaperones
2.3.2.1 H3.1/2-H4 Chaperone
2.3.2.2 H3.3-H4 Chaperones
2.3.2.3 CenH3CENP-A-H4 Chaperone
2.3.3 Other H3-H4 Chaperones
2.4 Deposition of H3-H4 Histones onto DNA
2.4.1 Deposition of New H3-H4 Histones
2.4.1.1 New H3.1/2-H4 Deposition by CAF-1
2.4.1.2 New H3.3-H4 Deposition by HIRA
2.4.1.3 New H3.3-H4 Deposition by DAXX-ATRX
2.4.1.4 New CenH3CENP-A-H4 Deposition by HJURP
2.4.2 Recycling of Old H3-H4 Histones
2.5 Concluding Remarks and Perspectives
References
Chapter 3: Histone H3K27M Mutation in Brain Tumors
3.1 Introduction
3.2 Role of Oncohistones H3.1K27M and H3.3K27M in Brain Tumors
3.3 Role of H3K27me3 Landscape Changes in Reprogramed Epigenome and Gene Expression in Brain Tumors
3.4 Involvement of H3K27ac Gain in the Epigenetic Landscape Changes in Brain Tumors
3.5 Influence of H3K27M and H3K27me3 Alterations on the Gene Expression in Brain Tumors
3.6 Different H3K27M-Driven Tumorigenic Mechanisms and Their Impacts on the Epigenome
3.7 Other H3K27M-Driven Tumorigenic Mechanisms in the Brain
3.8 H3K27M-DIPG Therapeutic Approaches and Strategies
3.8.1 The Reverse of H3K27ac Gain Approach
3.8.2 The Rescue of H3K27me3 Approach
3.8.3 Targeting the Activities of Residual EZH2 Approach
3.9 Conclusion, Perspective, and Future Direction
References
Chapter 4: Histone Mutations and Bone Cancers
4.1 Introduction
4.2 Bone Development, Homeostasis, and Bone Tumors
4.3 Histones and Epigenetics
4.3.1 Lysine Methylation of Histones
4.3.2 Nuclear Receptor SET Domain-Containing (NSD) Methyltransferase 2
4.3.3 Su(Var)3-9, Enhancer of Zeste, Trithorax Domain-Containing (SETD) Methyltransferase 2
4.4 Histone Mutations in Bone Tumors
4.4.1 Chondroblastomas
4.4.2 Giant Cell Tumors of Bone (GCTB)
4.4.3 Other Bone Tumors
4.5 Therapeutic Opportunities for Bone Tumors Harboring Oncohistones
4.6 Conclusion and Perspectives
References
Chapter 5: Histone H3G34 Mutation in Brain and Bone Tumors
5.1 Oncohistone H3G34R/V Mutation in Brain Tumors
5.2 Oncohistone H3G34W/L Mutation in Bone Tumors
5.3 Impact of H3G34 Mutation on the Epigenome
5.4 H3G34 Mutation and Genomic Instability
References
Chapter 6: Epigenetic-Targeted Treatments for H3K27M-Mutant Midline Gliomas
6.1 Introduction
6.2 The Histone and Epigenetic Landscape
6.3 H3K27M and Lysine Methylation
6.3.1 Molecular Biology of Lysine Methylation
6.3.2 Targeting Methylation
6.3.2.1 Demethylase Inhibition
6.3.2.2 Methyltransferase Inhibition
6.4 H3K27M and Acetylation
6.4.1 Molecular Biology of Lysine Acetylation
6.4.2 Targeting Acetylation
6.4.2.1 HDAC Inhibition
6.4.2.2 BET Inhibition
6.5 H3K27M and Phosphorylation
6.6 Future Considerations
6.7 Conclusions
References
Chapter 7: Histone Lysine-to-Methionine Mutation as Anticancer Drug Target
7.1 Introduction
7.2 Posttranscriptional Modifications of Histones
7.3 Histone H3 Mutations in Cancer
7.4 Histone Lysine 27 to Methionine Mutation
7.5 Mechanistic Insights into the Role of H3K27M
7.6 Histone Lysine 36 to Methionine Mutation
7.7 Therapeutic Targeting of Histone Lysine-to-Methionine Mutation
7.8 The Targeting Strategies for H3.3K27M
7.9 The Targeting Strategies for H3.3K36M
7.10 Conclusion and Perspective
References
