Epigenetics and Cancer: Mechanisms and Aberrant Reprogramming

This presentation explores the role of epigenetics in cancer, including DNA methylation, histone modification, nucleosome positioning, and micro-RNAs. It discusses the aberrant reprogramming of the epigenome in cancer, including changes in histone modifications and DNA methylation abnormalities. The presentation also covers epigenetic switching in cancer and its impact on tumorigenesis.

Epigenetics and
Cancer
Presented By:

OUTLI
NE
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1.0 Introduction
2.0 Epigenetic mechanisms in Cancer
 DNA Methylation
 Histone Modification
 Nucleosome positioning
 Micro-RNAs
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OUTLINE…
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3.0 Aberrant reprogramming of the epigenome
in cancer
 Changes in histone modifications in cancer
 DNA methylation abnormalities in cancer
 Epigenetic switching in cancer
Conclusion
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Introduction
 Epigenetic programming is important in the development
of mammals, and constant inheritance of epigenetic
structures (Verhoeven et al., 2016).
 Most of differentiation processes- activated and
maintained by epigenetics
 Thus marked by high level of stability and integrity
 Due to numerous interlocking response mechanisms
 Cancer-the expression of both epigenetic and genetic
alterations (Hatano et al., 2015)

Introduction…
Definition: Epigenetics
 Inherited alterations in gene manifestation activity and
manifestation that takes place without making modifying
the DNA sequences (Januar et al., 2015).
 Procedures involved in epigenetic control:
 DNA methylation,
 alterations in chromatin,
 physical alterations (nucleosome positioning), and
 micro-RNAs (Matzke and Mosher, 2014).

Literature Review :Epigenetic
mechanisms in Cancer
DNA methylation
 Significant element of the epigenetic process in
controlling gene manifestation and co-operating
with nucleosomes that regulate DNA packaging
influencing all the domains of DNA (Delpu et al.,
2013).
 Significant in the formation of 5-methylcytosine
(Smith and Meissner, 2013).
 DNMTs enzymes catalyse the alterations that occur
at 5-methylcytosine.

Literature Review :Epigenetic mechanisms
in Cancer…
DNA methylation…
 Types of DNMTs: DNMT1, DNMT3a, and DNMT3b
(Horvath, 2013).
 DNMT1 - protects the available methylation arrays after
DNA imitation
 DNMT3a & DNMT3b start methylation by targeting
unmethylated CpGs
 Expressions occur during embryogenesis
 least manifested in adult tissues (Johnson et al., 2012)
 Mechanisms are substantially modified in cancer due to
LOI (Jeltsch and Jurkowska, 2014).

Literature Review :Epigenetic mechanisms
in Cancer…
Histone modifications
 Made up of the nucleosome core that has a globular C-
terminal area and the N- terminal tail that is not
structured (Deindl et al., 2013).
 N-terminal tails of the histones go through several
posttranslational covalent alterations
 Alterations responsible for the regulation of the cellular
process such as imitation, transcription and restoration
(Zentner and Henikoff, 2013).

Literature Review :Epigenetic mechanisms
in Cancer…
Histone modifications…
 Epigenetic memory in a cell; ‘histocode’, regulates the
organization and function of varying areas of the
chromatin (Kalashnikova, 2016)
 Histone alterations are achieved through altering
chromatin accessibility or by integrating non-histone
effector protein
 which decodes the response encoded by the changing
arrays
 Inheritance process of this histone code yet to be explored

Literature Review :Epigenetic mechanisms
in Cancer…
Histone modifications…
 Histone alteration can result in suppression or initiation
 Dependent on the type of residues that are changed
and the nature of existing modifications (Zentner and
Henikoff, 2013
 E.g. H3K27 (H3K27me3) and H3K9 (H3K9me3) exists at
transcriptionally suppressed gene promoters
 Their alterations make up the two major silencing
process in mammalian cells
 Histone alternations: some determine cellular identity
(Ramos et al., 2013)).

Literature Review :Epigenetic mechanisms
in Cancer…
Histone modifications…
Epigenetic gene silencing mechanisms in mammals
Johnson et al. (2015)

Literature Review :Epigenetic mechanisms
in Cancer…
Nucleosome positioning
 Non-covalent process and have specific histone that determines
the manner in which chromatin makeup controls the activities of
the gene
 Nucleosomes control gene manifestation through modifying the
ease of access of governing DNA arrangements to transcription
elements (Struhl and Segal, 2013)
 NFRs exist at the fifth and third ends terminals of the genes
 offer the assembly and disassembly sites of the transcription
mechanism (Chen et al., 2013)

Literature Review :Epigenetic mechanisms
in Cancer…
Nucleosome positioning…
 Significant correlation between gene activation and a
direct upstream loss of a nucleosome of the transcription
commencement site (Coulon et al., 2013) .
 NFRs regulation is coordinated by chromatin-remodelling
multiplexes
 chromatin-remodelling multiplexes are ATP-
dependent, and
 play a key role in altering the accessibility of the DNA
sites of regulation (Narlikar et al., 2013)

Literature Review :Epigenetic mechanisms
in Cancer…
Nucleosome positioning…
 Association of DNA methylation and histone
alterations with the nucleosome remodelling
mechanism is vital in
 developing worldwide patterns of gene
expression and chromatin structure (Milagro et
al., 2013).
 Integration of histone alternatives such as H2A.Z
and H3.3, into nucleosomes affect gene activity
(Lawrence et al., 2016).

Literature Review :Epigenetic mechanisms
in Cancer…
Nucleosome positioning…
DNA methylation changes in cancer
Johnson et al. (2015)

Literature Review :Epigenetic mechanisms
in Cancer…
Nucleosome positioning…
 Association of DNA methylation and histone
alterations with the nucleosome remodelling
mechanism is vital in
 developing worldwide patterns of gene
expression and chromatin structure (Milagro et
al., 2013).
 Integration of histone alternatives such as H2A.Z
and H3.3, into nucleosomes affect gene activity
(Lawrence et al., 2016).

Literature Review :Epigenetic mechanisms
in Cancer…
Micro-RNAs
 Non-coding RNAs that play a key role in
gene manifestation via posttranscriptional
silencing of the genes of target
 Manifested in a tissue-specific way
 Regulate an extensive group of biological
mechanisms :cell proliferation and
differentiation
(Kawashima and Berger, 2014)

Literature Review :Epigenetic mechanisms
in Cancer…
Micro-RNAs…
 miRNAs in the genome of human and the
specific genes of target are on the increase
 Hence wide-ranging function in sustaining
worldwide patterns of gene expression (Di
Leva et al., 2013).
 Epigenetic processes also regulate the
manifestation of miRNAs (Ebrahimi et al.,
2014).
 Epigenetic processes within a cell can be
regulated by the miRNAs (Xu et al., 2014).

Literature Review :Aberrant reprogramming of the
epigenome in cancer
Changes in histone modifications in cancer
 Evidence of the massive loss of various
forms of histone acetylation (Johnson et
al., 2015)
 Big depletion of histone acetylation,
facilitated by Histone deacetylases
(HDACs), has led to gene repression.
 Epigenetic therapy focus on
overexpression of HDACs in multiple
cancer forms (Tang et al., 2013)

Literature Review :Aberrant reprogramming of the
epigenome in cancer
Changes in histone modifications in cancer…
 The levels of histone acetylation are maintained by
both HDACs and HATs
 These levels are changed in cancer
 Development of abnormal fusion proteins via
chromosomal alteration of HAT and associated
genes takes place in leukaemia (Mar et al., 2014)
 Cancer cells similarly indicate extensive
modifications in the patters of histone methylation
besides the alterations in histone acetylation.

Literature Review :Aberrant reprogramming of the
epigenome in cancer
DNA methylation abnormalities in cancer
 The commencement and development of cancer
go along with substantial alterations in DNA
methylation.
 DNA methylation formed the initial epigenetic
modifications noticed in cancer (Yang et al., 2013)
 Extensive genome hypomethylation and CpG island
promoter hypermethylation
 Used to identify cancerous epigenome (Matzke
and Mosher, 2014)

Literature Review :Aberrant reprogramming of the
epigenome in cancer
DNA methylation abnormalities in cancer…
 Continual repetition of DNA hypomethylation
causes an increase in the instability of the genome
(Matzke and Mosher, 2014)
 Genomic instability can be increased by the
activation and translocation processes caused by
the hypomethylation of retrotransposons (Chénais
et al., 2013)
 Most cancers in human have also indicated the loss
of DNA methylation and genomic instability

Literature Review :Aberrant reprogramming of the
epigenome in cancer
DNA methylation abnormalities in cancer…
 Hyperthymelation
 Also site-specific play a vital function in
tumorigenesis through silencing the genes that
subdue tumours
 Genes that suppress tumours e.g. p16, MLH1
and BRCA1
 These genes undergo silencing that is tumour-
specific and fostered through hypermethylation
(Plass et al., 2013).

Literature Review :Aberrant reprogramming of the
epigenome in cancer
Epigenetic switching in cancer
 Genetic changes in neoplastic cells inadequate to
explore carcinogenesis
 Because tumour cells manifest different
phenotypes in tumour development
 Cancer cells possess a modified epigenotype
different from the one they originate from
 Epigenetic switch- alterations in the level and
location of DNA methylation and histone changes

Literature Review :Aberrant reprogramming of the
epigenome in cancer
Epigenetic switching in cancer…
 The modifications affect the phenotype of the
neoplastic cells (Suvà et al., 2013).
 Most of the cancer cells obtain modified levels of
manifestation of epigenetic enzymes
 Tumour cells have a universal hypomethylated
genome (Matzke and Mosher, 2014)
 The CpGs in the duplicative DNA components and
regions of coding of the genes are methylated in
normal cells, not not methylated in tumour cells

Conclusion
 Significance of epigenetics in cancer has received a
lot of focus leading to advances in research
 Breakthrough in epigenomic methods - screening
of the methylation/acetylation state and miRNA
 Fundamental in the determination of the
biomarkers of other illnesses
 A proper comprehension of the association
between epigenetic and cancer will be beneficial in
planning improved treatment interventions.

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