Journal of Experimental & Clinical Cancer Research,
Год журнала:
2025,
Номер
44(1)
Опубликована: Янв. 7, 2025
Abstract
Background
Alternative
splicing
(AS)
is
a
process
that
facilitates
the
differential
inclusion
of
exonic
sequences
from
precursor
messenger
RNAs,
significantly
enhancing
diversity
transcriptome
and
proteome.
In
cancer,
pathogenic
AS
events
are
closely
related
to
cancer
progression.
This
study
aims
investigate
role
regulatory
mechanisms
in
gastric
(GC).
Methods
We
analyzed
various
tumor
samples
identified
hnRNPU
as
key
factor
GC.
The
effects
on
progression
were
assessed
through
vitro
vivo
experiments.
Gene
knockout
models
FTO
inhibitor
(meclofenamic
acid)
used
validate
interaction
between
their
impact
AS.
Results
found
serves
GC,
its
high
expression
associated
with
poor
clinical
prognosis.
Genetic
depletion
reduced
GC
Mechanistically,
m
6
A
demethylase
interacts
transcripts,
decreasing
modification
levels
hnRNPU,
which
leads
exon
14
skipping
MET
gene,
thereby
promoting
meclofenamic
acid
effectively
inhibited
cell
growth
both
vivo.
Conclusion
FTO/hnRNPU
axis
induces
aberrant
MET,
growth.
Targeting
may
interfere
abnormal
provide
potential
diagnostic
therapeutic
strategy
for
Graphical
Schematic
model
findings
this
work:
Aberrant
binds
FTO.
A-modified
transcripts
recognized
by
reader
YTHDF3
subsequently
demethylated
demethylation
enhances
stability
mRNA,
consequently
alternative
MET.
altered
pattern
ultimately
contributes
proliferation
cells.
Annual Review of Biochemistry,
Год журнала:
2023,
Номер
92(1), С. 145 - 173
Опубликована: Апрель 17, 2023
Over
the
past
decade,
mRNA
modifications
have
emerged
as
important
regulators
of
gene
expression
control
in
cells.
Fueled
large
part
by
development
tools
for
detecting
RNA
transcriptome
wide,
researchers
uncovered
a
diverse
epitranscriptome
that
serves
an
additional
layer
regulation
beyond
simple
sequence.
Here,
we
review
proteins
write,
read,
and
erase
these
marks,
with
particular
focus
on
most
abundant
internal
modification,
N6-methyladenosine
(m6A).
We
first
describe
discovery
key
enzymes
deposit
remove
m6A
other
discuss
how
our
understanding
has
shaped
views
modification
dynamics.
then
current
models
function
reader
knowledge
evolved.
Finally,
highlight
future
directions
field
questions
remain
unanswered.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Ноя. 26, 2024
Epigenetics
governs
a
chromatin
state
regulatory
system
through
five
key
mechanisms:
DNA
modification,
histone
RNA
remodeling,
and
non-coding
regulation.
These
mechanisms
their
associated
enzymes
convey
genetic
information
independently
of
base
sequences,
playing
essential
roles
in
organismal
development
homeostasis.
Conversely,
disruptions
epigenetic
landscapes
critically
influence
the
pathogenesis
various
human
diseases.
This
understanding
has
laid
robust
theoretical
groundwork
for
developing
drugs
that
target
epigenetics-modifying
pathological
conditions.
Over
past
two
decades,
growing
array
small
molecule
targeting
such
as
methyltransferase,
deacetylase,
isocitrate
dehydrogenase,
enhancer
zeste
homolog
2,
have
been
thoroughly
investigated
implemented
therapeutic
options,
particularly
oncology.
Additionally,
numerous
epigenetics-targeted
are
undergoing
clinical
trials,
offering
promising
prospects
benefits.
review
delineates
epigenetics
physiological
contexts
underscores
pioneering
studies
on
discovery
implementation
drugs.
include
inhibitors,
agonists,
degraders,
multitarget
agents,
aiming
to
identify
practical
challenges
avenues
future
research.
Ultimately,
this
aims
deepen
epigenetics-oriented
strategies
further
application
settings.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июнь 4, 2024
Abstract
Older
livers
are
more
prone
to
hepatic
ischaemia/reperfusion
injury
(HIRI),
which
severely
limits
their
utilization
in
liver
transplantation.
The
potential
mechanism
remains
unclear.
Here,
we
demonstrate
older
exhibit
increased
ferroptosis
during
HIRI.
Inhibiting
significantly
attenuates
HIRI
phenotypes.
Mass
spectrometry
reveals
that
fat
mass
and
obesity-associated
gene
(FTO)
expression
is
downregulated
livers,
especially
Overexpressing
FTO
improves
phenotypes
by
inhibiting
ferroptosis.
Mechanistically,
acyl-CoA
synthetase
long
chain
family
4
(ACSL4)
transferrin
receptor
protein
1
(TFRC),
two
key
positive
contributors
ferroptosis,
targets.
For
ameliorative
effect,
requires
the
inhibition
of
Acsl4
Tfrc
mRNA
stability
a
m6A-dependent
manner.
Furthermore,
nicotinamide
mononucleotide
can
upregulate
demethylase
activity,
suppressing
decreasing
Collectively,
these
findings
reveal
an
FTO-ACSL4/TFRC
regulatory
pathway
contributes
pathogenesis
HIRI,
providing
insight
into
clinical
translation
strategies
related
activity
improve
graft
function
after
donor
Abstract
Transfer
RNA
(tRNA)-derived
small
RNAs
(tsRNAs)
are
a
new
type
of
non-coding
(ncRNAs)
produced
by
the
specific
cleavage
precursor
or
mature
tRNAs.
tsRNAs
involved
in
various
basic
biological
processes
such
as
epigenetic,
transcriptional,
post-transcriptional,
and
translation
regulation,
thereby
affecting
occurrence
development
human
diseases,
including
cancers.
Recent
studies
have
shown
that
play
an
important
role
tumorigenesis
regulating
behaviors
malignant
proliferation,
invasion
metastasis,
angiogenesis,
immune
response,
tumor
resistance,
metabolism
reprogramming.
These
may
be
potential
targets
for
treatment.
Furthermore,
can
exist
abundantly
stably
bodily
fluids
(e.g.,
blood,
serum,
urine)
form
free
encapsulated
extracellular
vesicles,
intercellular
communication
microenvironment
(TME).
Meanwhile,
their
abnormal
expression
is
closely
related
to
clinicopathological
features
patients,
staging,
lymph
node
poor
prognosis
patients;
thus,
served
novel
liquid
biopsy
biomarker.
This
review
summarizes
discovery,
production,
analyzes
molecular
mechanisms
applications
therapy,
which
provide
strategies
early
diagnosis
targeted
therapy
tumors.
Drug
resistance
in
cancer
cells
significantly
diminishes
treatment
efficacy,
leading
to
recurrence
and
metastasis.
A
critical
factor
contributing
this
is
the
epigenetic
alteration
of
gene
expression
via
RNA
modifications,
such
as
N6-methyladenosine
(m6A),
N1-methyladenosine
(m1A),
5-methylcytosine
(m5C),
7-methylguanosine
(m7G),
pseudouridine
(Ψ),
adenosine-to-inosine
(A-to-I)
editing.
These
modifications
are
pivotal
regulating
splicing,
translation,
transport,
degradation,
stability.
Governed
by
"writers,"
"readers,"
"erasers,"
impact
numerous
biological
processes
progression,
including
cell
proliferation,
stemness,
autophagy,
invasion,
apoptosis.
Aberrant
can
lead
drug
adverse
outcomes
various
cancers.
Thus,
targeting
modification
regulators
offers
a
promising
strategy
for
overcoming
enhancing
efficacy.
This
review
consolidates
recent
research
on
role
prevalent
resistance,
with
focus
m6A,
m1A,
m5C,
m7G,
Ψ,
A-to-I
Additionally,
it
examines
regulatory
mechanisms
linked
underscores
existing
limitations
field.
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(14), С. 9731 - 9752
Опубликована: Июль 7, 2023
The
fat
mass
and
obesity-associated
protein
(FTO)
is
an
RNA
N6-methyladenosine
(m6A)
demethylase
highly
expressed
in
diverse
cancers
including
acute
myeloid
leukemia
(AML).
To
improve
antileukemia
drug-like
properties,
we
have
designed
44/ZLD115,
a
flexible
alkaline
side-chain-substituted
benzoic
acid
FTO
inhibitor
derived
from
FB23.
A
combination
of
structure–activity
relationship
analysis
lipophilic
efficiency-guided
optimization
demonstrates
that
44/ZLD115
exhibits
better
drug-likeness
than
the
previously
reported
inhibitors,
FB23
13a/Dac85.
Then,
shows
significant
antiproliferative
activity
leukemic
NB4
MOLM13
cell
lines.
Moreover,
treatment
noticeably
increases
m6A
abundance
on
AML
RNA,
upregulates
RARA
gene
expression,
downregulates
MYC
expression
cells,
which
are
consistent
with
knockdown.
Lastly,
antileukemic
xenograft
mice
without
substantial
side
effects.
This
promising
properties
can
be
further
developed
for
applications.
