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Histone lysine methyltransferase Wolf-Hirschhorn syndrome candidate 1 is involved in human carcinogenesis through regulation of the Wnt pathway.
[wolf-hirschhorn syndrome]
A
number
of
histone
methyltransferases
have
been
identified
and
biochemically
characterized
,
but
the
pathologic
roles
of
their
dysfunction
in
human
diseases
like
cancer
are
not
well
understood
.
Here
,
we
demonstrate
that
Wolf-
Hirschhorn
syndrome
candidate
1
(
WHSC
1
)
plays
important
roles
in
human
carcinogenesis
.
Transcriptional
levels
of
this
gene
are
significantly
elevated
in
various
types
of
cancer
including
bladder
and
lung
cancers
.
Immunohistochemical
analysis
using
a
number
of
clinical
tissues
confirmed
significant
up-regulation
of
WHSC
1
expression
in
bladder
and
lung
cancer
cells
at
the
protein
level
.
Treatment
of
cancer
cell
lines
with
small
interfering
RNA
targeting
WHSC
1
significantly
knocked
down
its
expression
and
resulted
in
the
suppression
of
proliferation
.
Cell
cycle
analysis
by
flow
cytometry
indicated
that
knockdown
of
WHSC
1
decreased
the
cell
population
of
cancer
cells
at
the
S
phase
while
increasing
that
at
the
G
(
2
)
/
M
phase
.
WHSC
1
interacts
with
some
proteins
related
to
the
WNT
pathway
including
β-catenin
and
transcriptionally
regulates
CCND
1
,
the
target
gene
of
the
β-catenin
/
Tcf-
4
complex
,
through
histone
H
3
at
lysine
36
trimethylation
.
This
is
a
novel
mechanism
for
WNT
pathway
dysregulation
in
human
carcinogenesis
,
mediated
by
the
epigenetic
regulation
of
histone
H
3
.
Because
expression
levels
of
WHSC
1
are
significantly
low
in
most
normal
tissue
types
,
it
should
be
feasible
to
develop
specific
and
selective
inhibitors
targeting
the
enzyme
as
antitumor
agents
that
have
a
minimal
risk
of
adverse
reaction
.