Epigenetic Cancer Therapy

Front Cover
Epigenetic Cancer Therapy
Copyright Page
Contents
List of contributors
1 Introduction
1 Introduction
2 Introduction to the area (key concepts)
3 Epigenetics and cancer
4 Targeting aberrant epigenetics
5 Issues to overcome/areas of concern
6 Future directions: translation to the clinic
References
1 Introduction and key concepts
2 Methylation and hydroxymethylation in cancer
1 Introduction
2 Epigenetics
2.1 Chromatin structure
2.2 Methylation in cellular homeostasis
2.2.1 Genomic distribution of DNA methylation
2.2.2 Functional role of DNA methylation
2.2.3 DNA methyltransferases
2.3 DNA demethylation in cellular homeostasis
2.4 DNA hydroxymethylation in cellular homeostasis
3 DNA methylation patterns in cancer
3.1 Hypermethylation in cancer
3.2 Hypomethylation in cancer
3.3 DNA hydroxymethylation in cancer
4 Aberrations of enzymes involved in DNA methylation homeostasis in cancer
4.1 DNA methyltransferases
4.2 Ten-eleven translocation proteins
4.3 Isocitrate dehydrogenases
4.4 Succinate dehydrogenases
5 Conclusions
List of abbreviations
References
3 Writers, erasers, and readers of DNA and histone methylation marks
1 Introduction
2 DNA methylation writers, erasers, and readers
2.1 DNMTs
2.2 TETs
2.3 Methyl-CpG-binding proteins
3 Histone lysine methylation writers, erasers, and readers
3.1 KMTs
3.2 KDMs
3.3 Methyllysine-binding domains
4 Arginine methylation writers, erasers, and readers
4.1 PRMTs
4.2 Putative RDMs
4.3 Methylarginine-binding proteins
5 Interplay between different methylation marks
6 Relevance of DNA methylation and histone methylation in cancer
6.1 DNA methylation and cancer
6.2 Histone methylation and cancer
7 Regulators of DNA and histone methylation as therapeutic targets
8 Conclusion
Acknowledgments
List of abbreviations
References
4 Oncohistones
1 Introduction
2 Histone H1 in tumorigenesis
3 H2 histone mutations in tumorigenesis
4 H3 histones in tumorigenesis (including histone H3 variants)
5 K27M
6 K36M
7 G34
8 H4 histones in tumorigenesis
9 Oncohistone mimics
10 Can we target oncohistones effectively?
11 Targeting oncohistone-altered pathways
12 Car-T-mediated targeting of oncohistone mutated cancer
13 Role of crispr in targeting oncohistones?
14 Conclusions
References
5 microRNA, epi-microRNA, and cancer
1 miRNA biogenesis and functionality
2 miRNA in cancer biology
3 miRNA: an epigenetic perspective
3.1 Epigenetic alteration of miRNA expression
3.2 Epi-miRNA
3.3 miRNA with epigenetic functions
4 miRNA epigenetic therapy
4.1 miRNA inhibition in cancer
4.2 miRNA replacement in cancer
4.3 Small-molecule-based miRNA modulation
4.4 miRNA therapy in clinical trials
5 Future perspectives
Acknowledgments
List of abbreviations
References
6 Long noncoding RNA in human cancers: to be or not to be, that is the question
1 lncRNAs in cancer have come of age
2 Regulation of rRNA biogenesis
2.1 Positive regulators of rDNA transcription and rRNA processing
2.2 Negative regulators of rDNA transcription and rRNA processing
3 Regulation of translation in cancer
4 Regulation of translation by lncRNAs
4.1 Dismantling the dogmas: coding–noncoding RNA in cancer
4.2 Targeting translation in cancer: the lesson of lncRNAs
5 Conclusion and perspective
References
7 The emerging roles of epitranscriptomic marks in cancer
1 Introduction
2 N6-methyladenosine in cancer
3 A-to-I RNA editing in cancer
4 5-Methylcytosine in cancer
5 N7-methylguanosine in cancer
6 2′-O-methylation in cancer
7 Pseudouridylation in cancer
8 N1-methyladenosine in cancer
9 3-Methylcytidine in cancer
10 Epitranscriptomics in diagnostics and therapeutics
10.1 Epitranscriptomic marks as diagnostic biomarkers
10.2 Therapeutic tools to correct mutations
11 Conclusions
List of abbreviations
References
8 Epigenomic profiling at genome scale: from assays and analysis to clinical insights
1 Introduction
2 Epigenomic profiling methods and the data generated by large-scale epigenomic projects
2.1 Genome-wide methylation
2.2 Alternative histones and histone modifications
2.3 Chromatin accessibility
2.4 Chromatin conformation
2.5 Gene expression including small and noncoding RNAs
2.6 Single-cell methods
2.7 Epigenomic projects and publicly available epigenomic data
3 Tools and analyses
3.1 Detecting differential methylation
3.2 Epigenome-wide association studies
3.3 Analysis of chromatin and histone states
3.4 Single-cell methods
3.5 Machine learning
3.6 Case studies
3.6.1 Case study 1: a multiomics signature for prostate cancer (https://github.com/BarryDigby/epi_chap)
3.6.1.1 Background
3.6.1.2 Dataset
3.6.1.3 Approach
3.6.1.4 Results
3.6.2 Case study 2: a multiomics approach to characterizing the immune cell landscape in renal cell carcinoma (https://gith...
3.6.2.1 Background
3.6.2.2 Dataset
3.6.2.3 Analysis approach
3.6.2.4 Results
3.6.2.5 Discussion
4 Conclusion
References
9 Environmental pollution, epigenetics, and cancer
1 Introduction
1.1 Pollution
1.2 Health effects of pollution
2 Pollutants
2.1 Particulate matter
2.2 Gaseous pollutants
2.2.1 Sulfur dioxide (SO2)
2.2.2 Nitrogen dioxide (NO2)
2.2.3 Ozone (O3)
2.2.4 Trichloroethylene
2.2.5 Methyl tert-butyl ether
2.2.6 Chloroform
2.2.7 Benzene
2.2.8 Acetaldehyde
2.3 Heavy metals
2.3.1 Nickel
2.3.2 Cadmium
2.3.3 Chromium
2.3.4 Lead
2.3.5 Mercury
2.3.6 Arsenic
2.4 Persistent organic pollutants
2.4.1 Dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene
2.4.2 Polybrominated diphenyl ethers
2.4.3 Perfluorooctanoic acid
2.4.4 Benzo[a]pyrene
2.5 Others
2.5.1 Bisphenol A
2.5.2 Aflatoxin B1
2.5.3 Radon
2.5.4 Microplastics
3 Conclusion
References
10 Synthetic biology and cell engineering—deriving new insights into cancer epigenetics
1 Introduction: an overview of epigenetic engineering
2 Genetic reporters: synthetic genes to monitor transcriptional regulation
3 Protein reporters: engineered proteins to track chromatin features in cancer cells
4 Epigenome editing: precise modification of chromatin
5 Epigenome actuation: streamlined chromatin-binding regulators of transcription
6 Conclusion
Glossary
Abbreviations
References
2 Epigenetics and cancer
11 Epigenetic targeted therapies in hematological malignancies
1 Introduction
2 Methylation as a clinical target in hematological disorders
2.1 DNA methylation
2.2 Hypomethylating agents
2.2.1 Azacitidine
2.2.2 Decitabine
2.2.3 IDH1/2 inhibitors
2.3 Methylation of histone targets
2.3.1 EZH2 inhibition
2.3.2 Alternative lysine methylation targets
3 Acetylation as a clinical target in hematological disorders
3.1 Histone deacetylation agents
3.1.1 HDAC inhibitors
3.1.2 JQ1/I-BET
4 Conclusion
Acknowledgements
References
12 Epigenetic therapy in lung cancer
1 Introduction
2 Overview of lung cancer
3 Epigenetic modifications in lung cancer
3.1 DNA methylation
3.2 Histone modifications
3.2.1 Histone methylation
3.2.2 Histone acetylation
3.3 Noncoding RNAs
4 Environmental factors affecting the lung epigenome
4.1 Cigarette smoking
4.2 Asbestos
4.3 Radon gas
5 Epigenetic targeting of lung cancer
5.1 Histone deacetylase inhibitors
5.2 DNA methyltransferase inhibitors
5.3 Bet inhibition
5.4 EZH2 inhibitors
5.5 Histone demethylase inhibitors
5.6 Combination strategies
6 Intratumor epigenetic heterogeneity and epigenetic therapies
7 Immunotherapy and epigenetics in lung cancer
8 Conclusions
References
13 Breast cancer epigenetics
1 Introduction
2 Epigenetic alterations in breast cancer
2.1 Histone modification
2.2 DNA methylation
2.3 MicroRNAs
3 Targeted epigenetic therapies
3.1 HDAC inhibitors
3.2 Preclinical activity of the HDAC inhibitors
3.3 Clinical investigation of HDAC inhibitors
3.3.1 Endocrine therapy combinations
3.3.2 Chemotherapy combinations
3.3.3 Immunotherapy combinations
4 DNMT inhibitors
4.1 Preclinical activity of the DNMT inhibitors
4.2 Clinical investigation of DNMT inhibitors
4.2.1 Epigenetic combinations
4.2.2 Chemotherapy and immunotherapy combinations
5 Newer epigenetic modifiers
6 Current status and future directions
Disclosure
Acknowledgements
References
14 Therapeutic applications of the prostate cancer epigenome
1 Introduction to prostate cancer
1.1 The androgen receptor signaling axis
1.2 Clinical management and treatment of prostate cancer
2 A snapshot of the prostate cancer epigeneome
2.1 The prostate cancer methylome
2.2 Histone modifications, variants, and epigenetic enzymes in prostate cancer
3 Epigenetic modulation of androgen receptor signaling
3.1 AR acetylation
3.2 AR methylation
4 Drugging the methylome for the treatment of castration-resistant prostate cancer
4.1 New classes of DNMT inhibitors
5 HDAC inhibitors for the treatment of castration-resistant prostate cancer
5.1 Synergistic activity
6 Targeting AR signaling by epigenetic drugs
7 Chemoprevention and neutraceutical therapies
7.1 Isothiocyanates
7.2 Curcumin
7.3 Phytoestrogens
7.4 Nutraceutical therapies in clinical trial
8 Conclusion
Acknowledgments
Abbreviations
References
15 Neuroblastoma
1 Neuroblastoma
2 Epigenetic changes
2.1 DNA methylation
2.1.1 Aberrant hypermethylation of CpGs within gene promoters
2.1.2 Genome-wide aberrant hypermethylation of CpGs islands assessment
2.2 Histone modifications
2.2.1 Histone acetylation/deacetylation
2.2.2 Histone methylation/demethylation
2.3 miRNA
2.3.1 miRNA expression patterns
2.3.2 Individual miRNAs
2.3.3 Epigenetic control of miRNA expression
2.4 Noncoding RNAs
2.4.1 Long noncoding RNAs
2.4.2 Circular RNAs
3 Epigenetic targeting agents
3.1 DNA methylation inhibitors
3.2 Inhibitors of histone modification enzymes
3.3 Differentiation therapeutics
4 miRNA-based therapeutics
4.1 miRNA replacement therapy
4.2 miRNA knockdown therapy
References
3 Targeting aberrant epigenetics
16 Epigenetic therapies—update on lysine methyltransferase/PRC complex inhibitors
1 Introduction
2 PRC enzyme mechanisms
3 PRC2 in cancer
4 Synthetic lethality
5 Tumor immunity
6 First-generation EZH2 inhibitors
7 Conformationally constrained EZH2 inhibitors
8 EED-targeted PRC2 modulators
9 EZH2 and EED degraders
10 Covalent EZH2 inhibitors
11 Clinical activity of EZH2 inhibitors
11.1 Tazemetostat: approved indications
11.2 Tazemetostat: ongoing trials
11.3 Other EZH2 inhibitors
12 Resistance mechanisms to EZH2 inhibition
13 Conclusions
References
17 Inhibitors of Jumonji-C domain-containing histone demethylases
1 Jumonji-C domain-containing family of writers
2 Role of JmjC proteins in human cancer
2.1 JmjC proteins in solid cancers
2.1.1 KDM2A and KDM2B
2.1.2 KDM3
2.1.3 KDM4
2.1.4 KDM5
2.1.5 KDM6
2.1.6 KDM7
2.2 JmjC proteins in hematological cancers
2.2.1 KDM2
2.2.2 KDM3
2.2.3 KDM4
2.2.4 KDM5
2.2.5 KDM6
3 Mechanism of inhibition
4 Chemical biology tools for the discovery of JmjC inhibitors
5 Development of selective inhibitors
5.1 2-OG competitive inhibitors
5.1.1 KDM2/7 inhibitors
5.1.2 KDM3 inhibitors
5.1.3 KDM6 inhibitors
5.1.4 KDM4 inhibitors
5.1.5 KDM5 inhibitors
5.1.6 Covalent inhibitors
6 JmjC inhibitors in cancer therapy
7 JmjC-based combinatorial approaches and drug resistance
8 Clinical trials
9 Current perspectives and future directions
Conflict of interest
Acknowledgments
Abbreviations
References
18 Emerging epigenetic therapies—lysine acetyltransferase inhibitors
1 Introduction
1.1 Lysine acetylation/acylation and its consequences in cancer
1.2 Rewiring of acetyl-CoA metabolism in cancer
2 Deregulation of KATs in cancer
2.1 KATs and cancer
2.1.1 p300/CBP family
2.1.2 GNAT family
2.1.3 MYST family
2.2 Autoacetylation in cancer progression
3 Lysine acetyltransferase: a potential target for therapeutics
3.1 Bisubstrate inhibitors
3.2 Natural KAT inhibitors and derivatives
3.2.1 Anacardic acid and derivatives
3.2.2 Polyphenols
3.2.3 Quinone
3.2.4 Alkaloids
3.2.5 Peptides
3.3 Synthetic KAT inhibitors
3.4 KAT bromodomain inhibitors
3.5 Inhibitors of KATs and effector protein interactions
3.6 Targeted degradation of KATs: PROTACs
4 Conclusion
Abbreviations
Acknowledgments
References
19 Epigenetic therapies: histone deacetylases
1 Introduction
2 Histone deacetylases
3 HDACs and cancer
4 HDACi
5 HDACi effects on tumor cells
6 FDA-approved HDACi
6.1 Vorinostat
6.2 Romidepsin
6.3 Belinostat
6.4 Panobinostat
6.5 Chidamide
7 Why HDACi failed in clinic for the treatment of solid tumors?
8 Short half-life
9 Toxicity
10 Metabolism
11 New perspectives
11.1 Vectorization
12 Dual inhibitor compounds
13 Combination with immunotherapies
14 Conclusion
References
4 Issues to overcome/areas of concern
20 Epigenetic intratumoral heterogeneity
1 Introduction
2 Using reference-based statistical methods to identify differentially methylated CpGs
3 Using reference-free statistical methods to identify differentially methylated CpGs
4 Statistical methods that identify differentially methylated cell types
5 Conclusion and future perspectives
References
21 Challenges for single-cell epigenetic analysis
1 Why single-cell epigenetics?
2 Current single-cell epigenetic assays and associated challenges
2.1 Single-cell ATAC-seq surveys the epigenome for accessible regions
2.2 Single-cell CUT&Tag surveys histone modification and TF-binding sites
2.3 Single-cell DNA methylation assays survey accessible CpG islands in the genome
3 Applications of single-cell epigenetics in cancer
3.1 Defining epigenetic changes underlying malignant transformation and oncogenesis
3.2 Characterizing epigenetics underpinnings of intratumoral heterogeneity
3.3 Identifying the gene-regulatory mechanisms of metastasis
3.4 Defining epigenetic signatures of the tumor microenvironment
4 Practical considerations for single-cell epigenetic analysis (and associated challenges)
4.1 Dissociation
4.2 Single-cell epigenomic platforms
4.3 Analysis: quality metrics
4.4 Analysis: single-cell epigenomic data matrix preparation
4.5 Analysis: clustering, annotation, and doublet removal
4.6 Analysis: feature-based analysis
4.7 Mechanistic insights from single-cell epigenomic analysis
4.7.1 Peak-to-gene linkages
4.7.2 Pseudotime trajectory analysis/velocity and potential
4.7.3 Inferring lineage from single-cell epigenomic data
4.7.4 CNV detection
5 Challenges and unanswered questions in epigenetic research in cancer
5.1 Open questions in cancer epigenomics
5.2 Identifying cancer cell types and cell states
5.3 Identifying tissue- and cell-of-origin
5.4 Handling data sparsity
6 Concluding remarks
References
22 Epigenetics of cisplatin resistance
1 Introduction
2 DNA methylation
2.1 DNA methylation changes associated with cisplatin resistance
3 Epigenetic readers, writers, and erasers and associated links with cisplatin response
3.1 Lysine acetyltransferases
3.2 Tip60/Kat5
3.3 KMTs
3.4 PRMTs
3.5 HDACs
3.6 KDMs
3.7 Epigenetic readers
3.8 BRCA1 complexes containing epigenetic readers/writers and erasers as a critical element in cisplatin resistance
3.8.1 BRCA1 complexes, the epigenetic machinery, and DNA damage response
3.8.2 BRCA1 is linked with sensitivity to cisplatin
3.8.3 The link between BRCA1, K-methyltransferases, and acquired cisplatin resistance
4 Noncoding RNAs (ncRNAs)
4.1 miRNAs associated with cisplatin resistance/sensitivity
4.2 epi-miRNAS and cisplatin sensitivity
4.3 lncRNAs associated with resistance/sensitivity
5 Cancer stem cells and cisplatin resistance
6 The epitranscriptome and cisplatin?
7 Targeting cisplatin resistance epigenetically?
7.1 Targeting HDACs
7.2 Targeting KDMs
7.3 Targeting KMTs
7.4 Targeting bet proteins and BrD containing epigenetic readers
7.5 Targeting PRMTs
7.6 Natural bioactives
8 Clinical trials
8.1 Circadian clocks/metronomic scheduling
8.2 Low-dose therapies as “epigenetic priming” events
9 Conclusions
Glossary
List of abbreviations
References
23 Emerging epigenetic therapies: protein arginine methyltransferase inhibitors
1 Introduction
2 PRMT protein summary
3 The role of PRMT proteins in cancer
3.1 Transcription
3.2 Splicing
3.3 mRNA regulation and translation
3.4 PRMTs and cancer stem cells
3.5 Important nonepigenetic roles
3.5.1 DNA damage response
3.5.2 Signal transduction
4 Discovery and efficacy of PRMT inhibitors
4.1 TYPE I PRMT inhibitors
4.2 TYPE II PRMT inhibitors
4.3 TYPE III PRMT inhibitors
4.4 Targeted use of PRMT inhibitors
5 Conclusions and future directions
List of abbreviations
References
5 Future directions: translation to the clinic
24 Personalized epigenetic therapy—chemosensitivity testing
1 Introduction
2 Chemoresistance in lymphomas
3 Epigenetically encoded chemoresistance
4 The evolving epigenetic landscape of lymphomas: treatment and aging
5 Implementing epigenetic therapy to chemosensitize lymphoma
6 What antitumoral effect to expect from epigenetic drugs?
7 Selecting the right drug for the right patient and vice versa
7.1 Cellular reprogramming
7.2 Synthetic lethality
8 Conclusions
Abbreviations
References
25 Epigenetic profiling in cancer: triage, prognosis, and precision oncology
1 Introduction
1.1 DNA methylation
1.2 Histone modifications
1.3 miRNAs
1.4 Feasibility for clinical implementation
2 Epigenetics testing in cancer screening and triage
2.1 Triaging HPV-positive women
2.2 Non-invasive screening alternatives for colorectal cancer
3 Epigenetics profiling for cancer prognosis
3.1 Improving treatment for acute myeloid leukemia by identifying prognosis biomarkers
3.2 Stratification of aggressive prostate cancer
4 Epigenetic signatures predict response to treatment
4.1 miRNAs in precision treatment of colorectal cancer patients
4.2 Precision treatment based on DNA methylation testing for breast cancer
4.3 Enhancing treatment success for metastatic castration-resistant prostate cancer using epigenetic markers
4.4 DNA methylation theragnostic may increase treatment success rate of glioblastoma treatment response
5 Conclusion and further directions
List of abbreviations
References
26 Epigenetic priming—fact or falacy?
1 Introduction
2 Epigenetic mechanisms of immune escape
3 Immune “cold” and “hot” tumors
4 Epigenetic therapy to warm up tumors
5 Epigenetic therapy to boost cancer immunity
6 Challenges to epigenetic priming
7 Conclusion
References
27 CRISPR, epigenetics, and cancer
1 Introduction
2 DNA methylation/demethylation
2.1 DNA methylation/demethylation processes and cancer
3 CRISPR-mediated DNA methylation
4 CRISPR-mediated DNA demethylation
5 Applications of CRISPR-mediated targeted methylation/demethylation in cancer
6 Histone modification
6.1 Histone posttranslational modifications and cancer
7 CRISPR-mediated histone methylation/demethylation
8 CRISPR-mediated histone acetylation/deacetylation
9 Applications of CRISPR-mediated histone modifications in cancer
10 CRISPR-dCas9-based synthetic transcription factors
11 Limitation and challenges
12 In vivo delivery of CRISPR systems
13 Off-target effects
14 Future perspectives
15 Conclusions
References
Index
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