epigenetics in cancer

mechanisms of epigenetics

DNA methylation
histone modification - phosphorylation, acetylation, methylation, SUMOylation, Ubiquitylation

DNA methylation

on cytosine
repels TFs via steric hindrance
repressor complexes bind and recruit HDACs

histone phosphorylation

H3S10 phos associated with mitosis and immediate early gene activation

histone acetylation

HaTs - writers
HDACs - erasers
BRDs - readers
on lysine, repulsion of DNA from nucleosome - transcriptional activation
H3k27Ac - active enhancers

histone methylation

HMTs - writers
chromodomain - readers
K3me3 - on, deposited by MLL4
K27/9me3 - off, deposited by EZH2

EZH2

repressive at K27
forms PRC2 complex
read by PRC1 which is also a writer - Ub to turn gene off

PRC consequences

chromatin compaction - RNAPII cant access
inhibition of H3K27Ac deposition - inhibits p300
stabilisation of chromatin loops and domains through long rage interactions between PRCs
protective functions against improper gene activation

histone SUMOylation

repressive
Ub like
recruits HDACs and co repressors

histone Ubiquitylation

H2B - promotes transcription elongation
H2A - associated with PRC2 mediated repression

nucleosome remodelling

sliding conferred by cofactors - requries ATP
histone exchange
eviction

phase separation

driven by IDRs that allow multivalent interactions
mechanism to concentrate epigenetic modellers at specific genomic loci
H3K27Ac promotes active condensates

superenhancers

TFs bind eDNA and recruit coactivators
IDR proteins phase separate to form transcriptional condensates

epigenetic mechanisms in cancer

global hypomethylation of DNA
aberrant ncRNA expression

target hypermethylation - inactivation of TSGs
disrupted histone modifications

ncRNA dysregulation

overexpression of oncomiRs
loss of TS miRs
epi miRs

epi miRs

miR-29 targets DNMT3 to revert aberrant DNA methylation
activates silenced TSGs in lung cancer models

global DNA hypomethylation

20-50% overall decrease in methylation of genome in cancer
promotes GIN
activation of LINE1 and overexpression of oncogenes

outcome of point mutation in EZH2

H3K27me3>me2
increased PcG
increased tumour growth

EZH2 mechanisms in cancer

Y64I point mutation = increased H3K27me3 = inactivation of TSGs
LOF mutation = decreased H3K27me3 = increase in sensitisation to oncogenic signalling
H3K27M mutation = inhibits PRC2 accumulation

MLL mechanisms in cancer

subunit composition switch = LOF = less TSG expression
MLL1 fusion protein = GOF = hox gene expression
MLL3/4 point mut

epigenetic addiction in PFA

lacks recurrent driver mutations
driven by global loss of H3K27me3 which activates growth signalling

epigenetic block in glioma

IDH mutations produce D2HG which inhibits dioxygenases that are necessary for demethylation of histones
cells frozen in progenitor state

epigenetics inducing phenotypic plasticity

dedifferentiation or transdifferentiation
basal cell carcinoma in the skin - switch epigenetically to wnt pathway to survive hedgehog loss
EMT

reverting function of writers - DNMTis

5 aza cytidine is cytosine analogue that incorporates into DNA and can’t be methylated

DNMT enzymes

DNMT1 = copies methylation during replication
DNMT3 = de novo methylation

reverting function of erasers - HDACis

opens chromatin at TSGs
use in AML-ETO fusion oncoproteins that recruit HDACs o downregulate CKIs and TSGs
e.g. vorinstat

reverting function of readers - BETis

BRD4 - bromodomain, reads ac, binds superenhancers and recruits ATFs
in cancer cells is hyperactive
BET inhibitors inhibit bromodomain or degrade protein

targeting HMTs

CPI 169 EZH2 inhibitor
re establishes transcription of TSGs leading to apoptosis of cancer cells
inhibits synthesis of SAM cofactor methyl donor by inhibiting SAH

EZH2 non canonical function

interacts with co activators via TAD - myc and p300
removing EZH2 therefore inhibits expression of oncogenic myc targets