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Epigenetic Cancer Therapy
Second Edition
Edited by
Steven G. Gray Thoracic Oncology Research Group, The Trinity St James’s Cancer Institute (TSJCI), St James’s Hospital, Dublin, Ireland; Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James’s Hospital, Dublin, Ireland; HOPE Directorate, St. James’s Hospital, Dublin, Ireland; School of Medicine, Trinity College Dublin, Dublin, Ireland; Thoracic Oncology Research Group, Central Pathology Laboratory, St. James’s Hospital, Dublin, Ireland
Series Editor
Trygve Tollefsbol
Contents
List of contributors ............................................................................................................................. xxi
CHAPTER 1 Introduction ...........................................................................................1
Steven G. Gray
1 Introduction ................................................................................................................ 1
2 Introduction to the area (key concepts) ..................................................................... 2
3 Epigenetics and cancer............................................................................................... 3
4 Targeting aberrant epigenetics................................................................................... 3
5 Issues to overcome/areas of concern ......................................................................... 4
6 Future directions: translation to the clinic................................................................. 4
References................................................................................................................... 5
Part 1 Introduction and key concepts
CHAPTER 2 Methylation and hydroxymethylation in cancer ................................ 11
Fazila Asmar, Linn Gillberg and Kirsten Grønbæk
1
Introduction .............................................................................................................. 11
2
Epigenetics ............................................................................................................... 12
2.1 Chromatin structure .......................................................................................... 12
2.2 Methylation in cellular homeostasis................................................................. 13
2.3 DNA demethylation in cellular homeostasis.................................................... 17
2.4 DNA hydroxymethylation in cellular homeostasis .......................................... 19
3 DNA methylation patterns in cancer ....................................................................... 20
3.1 Hypermethylation in cancer.............................................................................. 21
3.2 Hypomethylation in cancer............................................................................... 23
3.3 DNA hydroxymethylation in cancer................................................................. 23
4 Aberrations of enzymes involved in DNA methylation homeostasis
in cancer ................................................................................................................... 24
4.1 DNA methyltransferases ................................................................................... 25
4.2 Ten-eleven translocation proteins..................................................................... 26
4.3 Isocitrate dehydrogenases ................................................................................. 27
4.4 Succinate dehydrogenases ................................................................................ 28
5 Conclusions .............................................................................................................. 29
List of abbreviations................................................................................................. 29
References................................................................................................................. 31
CHAPTER 3 Writers, erasers, and readers of DNA and histone
methylation marks .............................................................................. 39
Jiameng Dan and Taiping Chen
1 Introduction .............................................................................................................. 40
2 DNA methylation writers, erasers, and readers....................................................... 40
2.1 DNMTs.............................................................................................................. 40
2.2 TETs.................................................................................................................. 43
2.3 Methyl-CpG-binding proteins........................................................................... 44
3 Histone lysine methylation writers, erasers, and readers ........................................ 45
3.1 KMTs ................................................................................................................ 45
3.2 KDMs ................................................................................................................ 48
3.3 Methyllysine-binding domains ......................................................................... 49
4 Arginine methylation writers, erasers, and readers ................................................. 50
4.1 PRMTs .............................................................................................................. 50
4.2 Putative RDMs.................................................................................................. 52
4.3 Methylarginine-binding proteins ...................................................................... 52
5 Interplay between different methylation marks....................................................... 52
6 Relevance of DNA methylation and histone methylation in cancer ...................... 53
6.1 DNA methylation and cancer ........................................................................... 53
6.2 Histone methylation and cancer ....................................................................... 54
7 Regulators of DNA and histone methylation as therapeutic targets....................... 55
8 Conclusion................................................................................................................ 56
Acknowledgments .................................................................................................... 56
List of abbreviations................................................................................................. 57
References................................................................................................................. 58
CHAPTER 4 Oncohistones....................................................................................... 65
Kristen Orumaa and Steven G. Gray
1 Introduction .............................................................................................................. 65
2 Histone H1 in tumorigenesis.................................................................................... 66
3 H2 histone mutations in tumorigenesis ................................................................... 67
4 H3 histones in tumorigenesis (including histone H3 variants) ............................... 68
5 K27M........................................................................................................................ 69
6 K36M........................................................................................................................ 70
7 G34 ........................................................................................................................... 71
8 H4 histones in tumorigenesis................................................................................... 73
9 Oncohistone mimics................................................................................................. 73
10 Can we target oncohistones effectively? ................................................................. 74
11 Targeting oncohistone-altered pathways ................................................................. 74
12 Car-T-mediated targeting of oncohistone mutated cancer ...................................... 75
13 Role of crispr in targeting oncohistones? ................................................................ 75
14 Conclusions .............................................................................................................. 76
References................................................................................................................. 76
CHAPTER 5 microRNA, epi-microRNA, and cancer............................................... 85
Michaela B. Kirschner, Harriet R. Walker and Hannah L. Moody
1 miRNA biogenesis and functionality....................................................................... 85
2 miRNA in cancer biology ........................................................................................ 88
3 miRNA: an epigenetic perspective .......................................................................... 90
3.1 Epigenetic alteration of miRNA expression..................................................... 90
3.2 Epi-miRNA ....................................................................................................... 92
3.3 miRNA with epigenetic functions .................................................................... 93
4 miRNA epigenetic therapy....................................................................................... 94
4.1 miRNA inhibition in cancer ............................................................................. 95
4.2 miRNA replacement in cancer ......................................................................... 98
4.3 Small-molecule-based miRNA modulation...................................................... 99
4.4 miRNA therapy in clinical trials ...................................................................... 99
5 Future perspectives................................................................................................. 100
Acknowledgments .................................................................................................. 101
List of abbreviations............................................................................................... 101
References............................................................................................................... 101
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