Epigenetics therapy

an introduction
R6

Definition
Epigenetics: all meiotically and mitotically
heritable changes in gene expression that are not
coded in the DNA sequence itself
DNA methylation
RNA associated silencing
Histone modification

Genotype and phenotype

Nature 2004;429:457-73

 Genes
Chromatin
Histone
nonhistone
chromosomal proteins

Nucleosome
Chromosome

Initiation of DNA
transcription

Methods to repress genes

Competitive DNA binding
Masking the activation surface
Direct interaction with the general
transcription factors
Recruitment of repressive chromatin
remodeling complex
Recruitment of histone deacetylases

Methods to repress genes

Methylation

Scaffold
protein

Histone
modification

Epigenetic diseases

Nature 2004;429:457-73

DNA methylation

DNA methylation
At promoter, DNA
methylation suppresses
transcription
DNA methyltransferase

With deamination, DNA

methylation induces C T
mutation

DNA methylation in cancer

Tumor suppressor
genes?

Nature Clin Pract Oncol

2005;2:S4-S11

Demethylation in cancer therapy

Nat Rev Drug Discov

2006;5:37-50

DNA methylation inhibitor, nucleoside

analogues and non-nucleoside analogues

Nat Rev Cancer 2006;5;37-50

Demetheylation effect of cytidine analogs in

fibroblast cell lines
Differentiation

Methylation

azacytidine
decitabine

Cell 1980;
20:85-93

Demethylation agent for MDS

Role of p15ink4b
p15 protein

Blood 2002;100:2957-64
Blood 2004;103:1635-40

Azacitidine improve response

rate* and time to leukemia
transformation in MDS but not
overall survival
JCO 2002;20:2429-40

Time to leukemia
transformation or death
P<0.0001

Overall survival p=0.10

Decitabine for MDS

Decitabine improves quality of life, decreases

RBC transfusion for MDS
Decitabine didnt improve AML-free survival or
overall survival(14.0vs 14.9mo, p= 0.636)
Cancer 2006;106:1794-80

NPM-ALK and STAT5 methylation

NPM-ALK kinase, t(2;5) in ALCL

Suppression of STAT 5 in ALCL cell line
siRNA of NPM-ALK reactivate STAT5
NPM-ALK transfection results in methlyation of STAT5
promoter inactivate STAT5

Nat Med 2007;13:1341-8

AML1/ETO and microRNA-223

AML1/ETO = t(8;21) in AM2L

Low level of miR-223 in AM2L t(8;21)
AML1/ETO induces methylation of miR-223 promoter
Inhibition of AML1/ETO reverses miR-223 expression
AML1-ETO(-)

AML1ETO(+)

Cancer cell 2007;12:457-66

Ras mediates methylation of

unrelated genes
The specificity of epigenetic change

Nature 2007;449:1073-78

Histone acetylation
(HDAC)

Role of histone
modification
DNA transcription
DNA repair
DNA replication

Cell 2007;128:693-705

Histone modification
the histone code

Acetylation
Methylation
Phosphorylation
Ubiquitylation
sumoylation

Nature
2007;447:407-12

Nature
2007;447:407-12

Nat Rev Drug Disc

2006;5:769-84

HDAC inhibitors

Nat Rev Cancer 2006;5;37-50

SAHA (vorinostat) in cutaneous T-cell lymphoma

JCO 2007;25:3109-15

SAHA in ovarian cancer

Gynecologic Oncology 2008 online published

HDAC inhibitor suppress ER activity in

estrogen dependent breast cancer cell line

trichostatin A
sensitizes estrogen
receptor -negative
breast cancer cells
to tamoxifen

Oncogene
2004;23:1724-36

HDAC inhibitor Trichostatin A induces

global and gene-specific DNA demethylation
Biochem. Pharmacol 2007;73:1297-1307

T24

Problems in epigenetics
agents in cancer therapy
Differentiation or cytotoxic agents?
Specificity and Selectivity of the
treatment targets?
Correction of epigenetic change and
underlying gene mutaion?
No survival benefit till now!!

Interchromosome regulation of genes

Nature 2007;447:413-7

Scaffold protein
SATB1
More higher
structure than
chromatin
Play important role
in T-cell
development
Nat Genetics 2006;38:1229-30

SATB1

SATB1 reprogrammes gene

expression to promote breast
tumour growth and metastasis

Nature 2008;452:187-193

Summary

Nature 2007;447:433-40

Summary
Methylation and HDAC
control of transcription through electric
change or 3-D conformational change of
chromatin
Control the phenotype
Application of cancer therapy?

Thank you
for
your attention

Decitabine induces ER gene

expression in ER(-) breast cancer
cell line(MDA-MB-231ELuc.6 cells)

Cancer Res
1995;55:2279-83

HDAC inhibitor and azacitidine together

induce ER expression in ER(-) breast
cancer line (MDA MB-231)

Cancer Res 2001;61:7025-29

Nature 2004;429:457-73

Cell 2007;128:655-68

Proteins that associate

preferentially with modified versions
of histone H3 and histone H4.

Crosstalk between histone modification

Cell 2007;128:693-705