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Acetate supplementation induces growth arrest of NG2/PDGFRα-positive oligodendroglioma-derived tumor-initiating cells.
[canavan disease]
Cancer
is
associated
with
globally
hypoacetylated
chromatin
and
considerable
attention
has
recently
been
focused
on
epigenetic
therapies
.
N-
acetyl-
L-
aspartate
(
NAA
)
,
the
primary
storage
form
of
acetate
in
the
brain
,
and
aspartoacylase
(
ASPA
)
,
the
enzyme
responsible
for
NAA
catalysis
to
generate
acetate
and
ultimately
acetyl-
Coenzyme
A
for
histone
acetylation
,
are
reduced
in
oligodendroglioma
.
The
short
chain
triglyceride
glyceryl
triacetate
(
GTA
)
,
which
increases
histone
acetylation
and
inhibits
histone
deacetylase
expression
,
has
been
safely
used
for
acetate
supplementation
in
Canavan
disease
,
a
leukodystrophy
due
to
ASPA
mutation
.
We
demonstrate
that
GTA
induces
cytostatic
G
0
growth
arrest
of
oligodendroglioma
-derived
cells
in
vitro
,
without
affecting
normal
cells
.
Sodium
acetate
,
at
doses
comparable
to
that
generated
by
complete
GTA
catalysis
,
but
not
glycerol
also
promoted
growth
arrest
,
whereas
long
chain
triglycerides
promoted
cell
growth
.
To
begin
to
elucidate
its
mechanism
of
action
,
the
effects
of
GTA
on
ASPA
and
acetyl-
CoA
synthetase
protein
levels
and
differentiation
of
established
human
oligodendroglioma
cells
(
HOG
and
Hs
683
)
and
primary
tumor
-derived
oligodendroglioma
cells
that
exhibit
some
features
of
cancer
stem
cells
(
grade
II
OG
33
and
grade
III
OG
35
)
relative
to
an
oligodendrocyte
progenitor
line
(
Oli
-
Neu
)
were
examined
.
The
nuclear
localization
of
ASPA
and
acetyl-
CoA
synthetase-
1
in
untreated
cells
was
regulated
during
the
cell
cycle
.
GTA-mediated
growth
arrest
was
not
associated
with
apoptosis
or
differentiation
,
but
increased
expression
of
acetylated
proteins
.
Thus
,
GTA-mediated
acetate
supplementation
may
provide
a
safe
,
novel
epigenetic
therapy
to
reduce
the
growth
of
oligodendroglioma
cells
without
affecting
normal
neural
stem
or
oligodendrocyte
progenitor
cell
proliferation
or
differentiation
.
Diseases
Validation
Diseases presenting
"considerable attention has recently been focused on epigenetic therapies"
symptom
canavan disease
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