Article

The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer

Department of Gastro-intestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan.
Oncology Reports (Impact Factor: 2.3). 11/2011; 27(3):637-42. DOI: 10.3892/or.2011.1547
Source: PubMed
ABSTRACT
Post-translational histone modifications are known to be altered in cancer tissues, and differences in the histone modification levels have recently been used to predict the clinical outcome in patients with certain types of cancer. In this study, we evaluated the immunohistochemical staining patterns of histone H3 dimethylation and acetylation in metachronous liver metastasis of colorectal carcinomas and examined its correlation with patient prognosis. Double 2 mm core tissue microarrays were made from 54 paraffin-embedded samples of liver metastasis from colorectal adenocarcinoma, and were examined by an immunohistochemical analysis of histone H3 lysine 4 (H3K4) dimethylation, histone, H3 lysine 9 (H3K9) dimethylation and histone H3 lysine 9 (H3K9) acetylation. Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were then examined for correlations with the clinicopathological parameters and clinical outcome. Dimethylation of H3K4 correlated with the tumor histological type (P=0.043), and acetylation of H3K9 correlated with the tumor histological type (P=0.016). In addition, lower levels of H3K4 dimethylation correlated with a poor survival rate (P=0.035). The multivariate survival analysis showed that the H3K4 dimethylation status is an independent prognostic factor for colorectal cancer patients (P=0.011). We suggest that the pattern of histone modification as detected by immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.

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ONCOLOGY REPORTS 27: 637-642, 2012
Abstract. Post-translational histone modications are known
to be altered in cancer tissues, and differences in the histone
modification levels have recently been used to predict the
clinical outcome in patients with certain types of cancer. In
this study, we evaluated the immunohistochemical staining
patterns of histone H3 dimethylation and acetylation in
metachronous liver metastasis of colorectal carcinomas and
examined its correlation with patient prognosis. Double 2 mm
core tissue microarrays were made from 54 parafn-embedded
samples of liver metastasis from colorectal adenocarcinoma,
and were examined by an immunohistochemical analysis of
histone H3 lysine 4 (H3K4) dimethylation, histone, H3 lysine
9 (H3K9) dimethylation and histone H3 lysine 9 (H3K9)
acetylation. Positive tumor cell staining for each histone
modication was used to classify patients into low- and high-
staining groups, which were then examined for correlations
with the clinicopathological parameters and clinical outcome.
Dimethylation of H3K4 correlated with the tumor histological
type (P=0.043), and acetylation of H3K9 correlated with the
tumor histological type (P=0.016). In addition, lower levels
of H3K4 dimethylation correlated with a poor survival rate
(P=0.035). The multivariate survival analysis showed that
the H3K4 dimethylation status is an independent prognostic
factor for colorectal cancer patients (P=0.011). We suggest that
the pattern of histone modication as detected by immuno-
histochemistry may be an independent prognostic factor for
metachronous liver metastasis of colorectal carcinomas.
Introduction
Colorectal cancer (CRC) is the third most common cancer and
the fourth leading cause of cancer-related deaths worldwide
(1). In spite of progress made in CRC chemotherapy, the
outcomes of CRC with distant metastasis still remain poor.
Liver metastasis of CRC is an important prognostic factor,
and occurs in 20-25% of CRC patients (2). Hepatic resection
is a potentially curative therapy for colorectal liver metastases.
However, recurrence develops in approximately 60-70% of all
such patients after hepatectomy, thus, suggesting that patients
with colorectal liver metastasis often do not benet from hepa-
tectomy. In addition, the prognostic factors for survival that can
be obtained from the resected specimens and the mechanism
of tumor progression of the metastases have not yet been fully
elucidated. Therefore, it is important to identify the specic
biomarker of CRC outcomes, especially for patients with liver
metastases.
DNA methylation and histone modification are major
epigenetic mechanisms controlling gene regulation, and they
are frequently altered in cancer (3). Changes in DNA methyla-
tion are closely related to patterns of histone modication (4).
Cellular patterns of histone modications have been reported
as providing independent prognostic information for several
cancers, including prostate (5,6), kidney (6), lung (6-8), gastric
(9), ovarian (10), pancreatic (10,11), esophageal (12,13) and
breast cancers (10,14). Modication of histones by methyla-
tion and acetylation at lysine residues is generally associated
with gene inactivation or silencing (15-19). In CRC patients,
it has also been previously reported that reduced H3 lysine
4 methylation and increased H3 lysine 9 methylation play a
critical role in the maintenance of promoter DNA methylation-
associated gene silencing (15). However, to date, there have
been no reports on the prognostic signicance of global histone
modications in cases of CRC, including liver metastasis.
In this st udy, we cla ssi ed t he expression levels of the histone
dimethylation in 54 pairs of the liver metastases obtained
from patients with metachronous liver metastasis of CRC.
To evaluate the clinical signicance of histone modication,
The global histone modication pattern correlates with overall
survival in metachronous liver metastasis of colorectal cancer
HIROSHI TAMAGAWA
1
, TAKASHI OSHIMA
4
, MANABU SHIOZAWA
1
, SOICHIRO MORINAGA
1
,
YOSHIYASU NAKAMURA
3
, MITSUYO YOSHIHARA
3
, YUJI SAKUMA
3
, YOICHI KAMEDA
2
,
MAKOTO AKAIKE
1
, MUNETAKA MASUDA
5
, TOSHIO IMADA
5
and YOHEI MIYAGI
3
Departments of
1
Gastrointestinal Surgery and
2
Pathology, Kanagawa Cancer Center, and
3
Division of
Molecular Pathology and Genetics, Kanagawa Cancer Center Research Institute, Yokohama 241-0815;
4
Gastrointestinal Center, Yokohama City University Medical Center, Yokohama 232-0024;
5
Department of Surgery, Yokohama City University, Yokohama 236-0004, Japan
Received September 12, 2011; Accepted October 21, 2011
DOI: 10.3892/or.2011.1547
Correspondence to: Dr Hiroshi Tamagawa, Department of Gastro-
intestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku,
Yokohama 241-0815, Japan
E-mail: tamagawah@kcch.jp
Key words: histone modification, prognostic factor, immuno-
histochemistry, liver metastasis, H3K4, H3K9, colorectal cancer
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    • "Global hypoacetylation of H4K12 and H3K18 has been observed in undifferentiated colorectal adenocarcinomas, whereas their acetylation was increased in well-differentiated tumours [24]. Contrary to these findings, the H3K9 hypoacetylation status was positively correlated with tumour histological type and low H3K9Ac was observed in well-differentiated tu- mours [25]. To the best of our knowledge, aberrant H3K27Ac levels in CRC have not been reported to date. "
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  • [Show abstract] [Hide abstract] ABSTRACT: Epigenetic regulation of gene expression has provided colorectal cancer (CRC) pathogenesis with an additional trait during the past decade. In particular, histone post-translational modifications set up a major component of this process dictating chromatin status and recruiting non-histone proteins in complexes formed to "handle DNA". In CRC, histone marks of aberrant acetylation and methylation levels on specific residues have been revealed, along with a plethora of deregulated enzymes that catalyze these reactions. Mutations, deletions or altered expression patterns transform the function of several histone-modifying proteins, further supporting the crucial role of epigenetic effectors in CRC oncogenesis, being closely associated to inactivation of tumor suppressor genes. Elucidation of the biochemical basis of these new tumorigenic mechanisms allows novel potential prognostic factors to come into play. Moreover, the detection of these changes even in early stages of the multistep CRC process, along with the reversible nature of these mechanisms and the technical capability to detect such alterations in cancer cells, places this group of covalent modifications as a further potential asset for clinical diagnosis or treatment of CRC. This review underlines the biochemistry of histone modifications and the potential regulatory role of histone-modifying proteins in CRC pathogenesis, to date. Furthermore, the underlying mechanisms of the emerging epigenetic interplay along with the chemical compounds that are candidates for clinical use are discussed, offering new insights for further investigation of key histone enzymes and new therapeutic targets.
    No preview · Article · May 2012 · The international journal of biochemistry & cell biology
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    Full-text · Article · Dec 2012 · Cancer Epidemiology Biomarkers & Prevention
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