Download Gene Section CHD5 (chromodomain helicase DNA binding protein 5)

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Atlas
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Huret JL, Laï JL
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Gene Section
Review
CHD5 (chromodomain helicase DNA binding
protein 5)
Venkatadri Kolla, Mayumi Higashi, Tiangang Zhuang, Garrett M Brodeur
Children's Hospital of Philadelphia, Oncology Research, CTRB Rm 3018, 3501 Civic Center Blvd,
Philadelphia, PA 19104, USA (VK, MH, TZ, GMB)
Published in Atlas Database: January 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/CHD5ID44521ch1p36.html
DOI: 10.4267/2042/47336
This article is an update of :
Brodeur GM, White PS. CHD5 (Chromodomain-helicase-DNA binding protein 5). Atlas Genet Cytogenet Oncol Haematol
2010;14(10):934-936.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
finger motifs are thought to play roles in chromatinassociated
transcriptional
regulation,
whereas
chromodomains are frequently observed in proteins
involved in recruitment of transcriptional regulatory
complexes.
The central portion of the protein includes a predicted
DEAH-box type helicase domain (703-999) and a
putative SNF2 domain (1054-1138). DEAH ATP
helicases are ATP-dependent and are usually associated
with nucleic acid unwinding. SNF2 domains are
commonly observed in, although not restricted to,
proteins involved in chromatin unwinding, DNA repair
and recombination, and transcriptional regulation.
A number of potential nuclear localization signals are
also present (50-67, 54-71, 97-114, 100-117, 240-257,
253-270, 918-935) (Thompson et al., 2003).
Identity
Other names: DKFZp434N231, KIAA0444
HGNC (Hugo): CHD5
Location: 1p36.31
DNA/RNA
Description
Gene is encoded by 42 exons, spanning 78331 bp
(NCBI).
mRNA: NM_015557.2.
Transcription
The CHD5 cDNA sequence spans 9646 bp, with a 5'
UTR of 100 bp, a single open reading frame of 5865
bp, and a 3' UTR of 3681 bp (Thompson et al., 2003).
Expression
Detectable expression of CHD5 was limited to all
neural-derived tissues (fetal brain, total brain,
cerebellum) and adrenal gland, with no expression
detected in placenta, liver, fetal liver, spleen, bone
marrow, thyroid, thymus, salivary gland, stomach,
pancreas, small intestine, colon, or prostate (Thompson
et al., 2003; Okawa et al., 2008; Wikimedia
Commons).
Expression is also found in testis (Potts et al., 2011;
BioGPS; Brodeur, unpublished observations).
Pseudogene
None known.
Protein
Description
The 5' portion of CHD5 is predicted to contain two
zinc-fingers of the PHD class (amino-acid positions
345-390 and 418-463), followed closely by two
chromodomains (510-525 and 596-625). PHD zinc-
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
392
CHD5 (chromodomain helicase DNA binding protein 5)
Kolla V, et al.
The functional domains of the chromodomain-helicase-DNA binding protein 5 (CHD5) are shown above. There are two PHD type zinc
fingers, two chromodomains, a split DEAH-box ATP-helicase domain, and a poorly defined DNA binding domain (NP_056372.1).
in a panel of 101 primary tumors (Fujita et al., 2008).
These data suggest that CHD5 is a bona fide tumor
suppressor gene in neuroblastomas. Deletion of 1p36 is
associated with loss of CHD5 expression, and the
CHD5 promoter is preferentially methylated in lines
with 1p36 deletion. Low CHD5 expression is also
associated with a worse outcome in neuroblastoma
patients. Furthermore, low CHD5 expression is
associated with a worse outcome in neuroblastoma
patients (Koyama et al., 2012). Most recent protein
expression studies showed that CHD5 acted as
immunohistochemical marker in NB in 90 primary NTs
suggesting a strong association of CHD5 expression
with favorable prognostic variables that were tested in a
blind set of 32 NB tumors (Garcia et al., 2010). In
addition to these observations this brain specific protein
has been shown to regulate neural gene expression
(Potts et al., 2011). Moreover, CHD5 forms a NuRD
complex similar to Mi2β/CHD4, and it presumably acts
as chromatin remodeling enzyme in regulating gene
expression (Kolla et al., unpublished observations).
Localisation
Intracellular expression is preferentially
(Brodeur, unpublished observations).
nuclear
Function
CHD family proteins are thought to play a role in
chromatin remodeling. CHD5 is most homologous to
CHD3 and CHD4, which participate in the formation of
a nucleosome remodeling and deacetylation (NuRD)
complex, in association with other proteins. This
complex is generally thought to repress transcription.
Homology
Strongest homology is to CHD3 and CHD4, with
weaker homology to CHD1, CHD2, CHD6, CHD7,
CHD8 and CHD9.
Mutations
Note
No examples of homozygous inactivation have been
identified, and no nonsense or frameshift mutations
have been identified in any cancers to date. Several
missense mutations have been detected, but it is unclear
if any of these have an effect on the function of the
protein (Okawa et al., 2008; Fujita et al., 2008; Ng et
al., 2008; Koyama et al., 2012).
Gliomas
Note
CHD5 is one of several genes that maps to the 700 kb
region of consistent deletion in 17 glioma cell lines
(Law et al., 2005). Loss of CHD5 expression is
associated with deletion of 1p36 in a panel of 54 glial
tumors (Bagchi et al., 2007). These data are consistent
with a role for CHD5 as a tumor suppressor gene in
these tumors.
Implicated in
Neuroblastoma
Note
CHD5, a new member of the chromodomain gene
family, is preferentially expressed in the nervous
system (Thompson et al., 2003). CHD5 maps to
1p36.3, a region of consistent deletion in
neuroblastoma and other tumors (White et al., 2005).
CHD5 is one of 23 genes that map to the 800 kb region
of consistent deletion on 1p36.3 in an analysis of over
1200 primary neuroblastomas (Okawa et al., 2008).
Functional analysis of CHD5 after transfection into
neuroblastoma cell lines demonstrates that CHD5
functions as a tumor suppressor gene, suppressing both
clonogenicity and tumorigenicity. The promoter was
methylated especially between -780 and -450 in
neuroblastoma cell lines with 1p36 deletions, but not
those with two copies of CHD5. Furthermore, high
CHD5 expression is highly correlated with favorable
clinical and biological risk features as well as outcome
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Melanoma
Note
A subset of malignant melanoma families show linkage
to 1p36, and CHD5 is a tumor suppressor gene that
maps to this region. However, screening of CHD5 for
mutations in eight melanoma-prone families linked to
1p36 revealed no deleterious coding or splice site
mutations (Ng et al., 2008). Moreover, to understand
the role of CHD5 in familial melanoma, studies have
shown CHD5 variants in familial cutaneous melanoma
that could block or alter the ability of CHD5 to regulate
the cell cycle pathway and to effect cellular control.
But only one out of 47 families studied has this variant.
Thus, it appears to be a rare event and further
elaborative studies are required to confirm the role of
CHD5 in melanoma pathogenesis (Lang et al., 2011).
This suggests that CHD5 is not a major melanoma or
393
CHD5 (chromodomain helicase DNA binding protein 5)
Kolla V, et al.
subcutaneous melanoma susceptibility gene, at least in
the families screened.
Lung cancer
Note
Role of CHD5 in a lung cancer and epigenetic
modification as well as its tumor-suppressive capability
has been studied by measuring CHD5 mRNA and
protein expression in lung cancer cells and tissues.
CHD5 expression ranged from low to absent in the
lung cancer cell lines and tissues examined correlated
the results with CHD5 promoter hypermethylation.
Clonogenicity and tumor growth were abrogated in
lung cancer cell lines A549 and H1299 upon restoration
of CHD5 expression (Zhao et al., 2011). These results
suggest that CHD5 serves as a potential tumor
suppressor gene in lung cancer that is inactivated via an
epigenetic mechanism.
Ovarian cancer
Note
Mutation and methylation analysis of CHD5 gene was
undertaken in 123 ovarian cancers, whereas no such
mutations were identified in 60 primary breast cancers.
Somatic heterozygous missense mutations were
identified in 3 samples, and promoter methylation was
identified in another 3 of 45 samples tested (Gorringe
et al., 2008). Recently, correlation of CHD5 with
clinicopathological features of the tumor is also shown
by quantitative RT-PCR methods. CHD5 is
downregulated in a certain number of ovarian cancers
and appears to be an adverse predictor candidate of
ovarian cancer disease-free and total survival (Wong et
al., 2011). These data suggest that CHD5 may play a
role as a tumor suppressor gene in a subset of ovarian
cancers, but there may be other suppressors on 1p36 as
well.
Prostate cancer
Note
Comprehensive genomic survey has been conducted for
somatic events in systemic metastatic prostate tumors
using both high-resolution copy number analysis and
targeted mutational survey of 3508 exons from 577
cancer-related genes using next generation sequencing.
Novel somatic point mutations have been shown in
CHD5 along with MTOR, BRCA2, and ARHGEF12
(Robbins et al., 2011). This study indicates a deep
genomic analysis of advanced metastatic prostate
tumors that lead to somatic alterations, possibly
contributing to lethal prostate cancer.
Colorectal cancer
Note
The methylation status of a set of cancer-related genes
was studied in 102 colon cancers from Iranian and
African-American populations (51 each). The
methylation status of the promoters of three genes
(CHD5, ICAM5 and GPNMB) was significantly higher
in cancers from the African-American population
compared to the Iranian patients (Mokarram et al.,
2009). This suggests that these genes may play a role in
the incidence or aggressiveness of colorectal cancer in
this population.
Laryngeal squamous cell carcinoma
Note
Tumor suppressive role of CHD5 has been observed in
65 patients with laryngeal squamous cell carcinomas
(LSCC) where both CHD5 RNA and protein
expressions were significantly lower. These
observations were also in correlation with promoter
hypermethylation. Interestingly, ectopic expression of
CHD5 in laryngeal cancer cells led to significant
inhibition of growth and invasiveness (Wang et al.,
2011). These data suggest that CHD5 acts as a tumor
suppressor gene that is epigenetically downregulated in
LSCC.
Gastric cancer
Note
The methylation status of the CHD5 promoter was
examined in 15 primary gastric cancers and 7 gastric
cancer cell lines. CHD5 expression was downregulated
in 7/7 cell lines, and methylation of the promoter was
found in all 7 lines, and a similar correlation was found
in 11/15 primary tumors. Ectopic expression of CHD5
led to significant growth inhibition. These results
suggest that CHD5 plays a role as a tumor suppressor
gene in gastric cancer, and its expression may be downregulated epigenetically.
Breakpoints
Note
None known.
Various cancers (colon cancer, breast
cancer, gliomas)
References
Note
The promoter of all nine current members of the CHD
family were analyzed for methylation, and only the
CHD5 promoter showed CpG hypermethylation in a
subset of primary cancers, especially colon cancer,
breast cancer and gliomas (Mulero-Navarro and
Esteller, 2008). Thus, epigenetic inactivation of CHD5
expression may contribute to the pathogenesis of
various cancers.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Thompson PM, Gotoh T, Kok M, White PS, Brodeur GM.
CHD5, a new member of the chromodomain gene family, is
preferentially expressed in the nervous system. Oncogene.
2003 Feb 20;22(7):1002-11
Law ME, Templeton KL, Kitange G, Smith J, Misra A,
Feuerstein BG, Jenkins RB. Molecular cytogenetic analysis of
chromosomes 1 and 19 in glioma cell lines. Cancer Genet
Cytogenet. 2005 Jul 1;160(1):1-14
394
CHD5 (chromodomain helicase DNA binding protein 5)
Kolla V, et al.
White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok
M, Winter C, Gregory SG, Hogarty MD, Maris JM, Brodeur GM.
Definition and characterization of a region of 1p36.3
consistently deleted in neuroblastoma. Oncogene. 2005 Apr
14;24(16):2684-94
Casala C, Galván P, de Torres C, Mora J, Lavarino C.
Expression of the neuron-specific protein CHD5 is an
independent marker of outcome in neuroblastoma. Mol
Cancer. 2010 Oct 15;9:277
Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D,
Bredel M, Vogel H, Mills AA. CHD5 is a tumor suppressor at
human 1p36. Cell. 2007 Feb 9;128(3):459-75
Lang J, Tobias ES, Mackie R. Preliminary evidence for
involvement of the tumour suppressor gene CHD5 in a family
with cutaneous melanoma. Br J Dermatol. 2011
May;164(5):1010-6
Fujita T, Igarashi J, Okawa ER, Gotoh T, Manne J, Kolla V,
Kim J, Zhao H, Pawel BR, London WB, Maris JM, White PS,
Brodeur GM. CHD5, a tumor suppressor gene deleted from
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2;100(13):940-9
Potts RC, Zhang P, Wurster AL, Precht P, Mughal MR, Wood
WH 3rd, Zhang Y, Becker KG, Mattson MP, Pazin MJ. CHD5,
a brain-specific paralog of Mi2 chromatin remodeling enzymes,
regulates expression of neuronal genes. PLoS One.
2011;6(9):e24515
Gorringe KL, Choong DY, Williams LH, Ramakrishna M,
Sridhar A, Qiu W, Bearfoot JL, Campbell IG. Mutation and
methylation analysis of the chromodomain-helicase-DNA
binding 5 gene in ovarian cancer. Neoplasia. 2008
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mutational analysis reveals novel somatic events in metastatic
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JM, David A, Le Caignec C. Complex constitutional
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child with neonatal neuroblastoma. Eur J Med Genet. 2008
Nov-Dec;51(6):679-84
Wang J, Chen H, Fu S, Xu ZM, Sun KL, Fu WN. The
involvement of CHD5 hypermethylation in laryngeal squamous
cell carcinoma. Oral Oncol. 2011 Jul;47(7):601-8
Wong RR, Chan LK, Tsang TP, Lee CW, Cheung TH, Yim SF,
Siu NS, Lee SN, Yu MY, Chim SS, Wong YF, Chung TK.
CHD5 Downregulation Associated with Poor Prognosis in
Epithelial Ovarian Cancer. Gynecol Obstet Invest.
2011;72(3):203-7
Mulero-Navarro S, Esteller M. Chromatin remodeling factor
CHD5 is silenced by promoter CpG island hypermethylation in
human cancer. Epigenetics. 2008 Jul-Aug;3(4):210-5
Ng D, Yang XR, Tucker MA, Goldstein AM. Mutation screening
of CHD5 in melanoma-prone families linked to 1p36 revealed
no deleterious coding or splice site changes. BMC Res Notes.
2008 Sep 19;1:86
Zhao R, Yan Q, Lv J, Huang H, Zheng W, Zhang B, Ma W.
CHD5, a tumor suppressor that is epigenetically silenced in
lung cancer. Lung Cancer. 2012 Jun;76(3):324-31
Okawa ER, Gotoh T, Manne J, Igarashi J, Fujita T, Silverman
KA, Xhao H, Mosse YP, White PS, Brodeur GM. Expression
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Jan 31;27(6):803-10
Cai C, Ashktorab H, Pang X, Zhao Y, Sha W, Liu Y, Gu X.
MicroRNA-211 expression promotes colorectal cancer cell
growth in vitro and in vivo by targeting tumor suppressor
CHD5. PLoS One. 2012;7(1):e29750
Koyama H, Zhuang T, Light JE, Kolla V, Higashi M, McGrady
PW, London WB, Brodeur GM. Mechanisms of CHD5
Inactivation in neuroblastomas. Clin Cancer Res. 2012 Mar
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This article should be referenced as such:
Wang X, Lau KK, So LK, Lam YW. CHD5 is down-regulated
through promoter hypermethylation in gastric cancer. J Biomed
Sci. 2009 Oct 19;16:95
Kolla V, Higashi M, Zhuang T, Brodeur GM. CHD5
(chromodomain helicase DNA binding protein 5). Atlas Genet
Cytogenet Oncol Haematol. 2012; 16(6):392-395.
Garcia I, Mayol G, Rodríguez E, Suñol M, Gershon TR, Ríos J,
Cheung NK, Kieran MW, George RE, Perez-Atayde AR,
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
395