Clinical Study
Downregulation of chromatin remodeling factor CHD5 is associated with a poor prognosis in human glioma

https://doi.org/10.1016/j.jocn.2012.07.021Get rights and content

Abstract

Chromodomain helicase DNA-binding protein 5 (CHD5), a member of the CHD family, is involved in key cellular processes including chromatin remodeling, cell cycle regulation, and cellular adhesion. Recent studies have demonstrated that CHD5 is the product of a novel tumor suppressor gene and is implicated in certain tumor types. However, the clinicopathological significance of CHD5 expression in human malignant gliomas remains unclear. To address this problem, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured using real-time quantitative polymerase chain reaction (RT–PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors or prognosis of glioma patients was statistically analyzed. Genetic and protein expression of CHD5 were downregulated in glioma tissues compared to corresponding non-neoplastic brain tissues (both p < 0.001). Additionally, decreased expression of CHD5 in glioma was significantly associated with pathological grade (p = 0.007); high pathological grade was associated with low CHD5 expression. Loss of CHD5 protein expression was also significantly correlated with a low Karnofsky performance scale score (p = 0.01). Moreover, overall survival of patients with low CHD5 protein expression was dramatically shorter than those of patients with high CHD5 protein expression (p = 0.003). Multivariate Cox regression analysis indicated that CHD5 expression was an independent prognostic factor for patients with gliomas (p = 0.01). In conclusion, these data offer convincing evidence for the first time that CHD5 might act as a tumor suppressor in glioma, may act as a regulator of aggressive development, and is a candidate prognostic marker for this malignancy.

Introduction

Gliomas are the most common malignancy in the central nervous system for both children and adults. The glioma family includes well-differentiated low grade astrocytomas [World Health Organization (WHO) grade I–II], anaplastic astrocytomas (WHO grade III) and glioblastoma multiforme (GBM, WHO grade IV).1 Despite great progress in therapeutic technologies, including surgery, radiotherapy, photodynamic therapy,2, 3 and chemotherapy, survival remains poor, with less than 3% 5-year survival rate for patients with GBM.4 Recent studies have indicated that age, Karnofsky performance scale (KPS) score, histologic grade, and tumor necrosis are important prognostic factors for gliomas.5 However, the prognosis of both high-and low-grade tumors remains heterogeneous. Curran et al.6 demonstrated that the survival of patients with high-grade gliomas ranges from 5–59 months, and some patients with low-grade tumors have a poorer outcome than expected.

It is widely accepted that both activation of proto-oncogenes and inactivation of tumor suppressor genes are involved in glioma progression. To understand genetic and molecular pathogenic changes during the development of gliomas, it is therefore important to identify novel diagnostic and prognostic markers.

The chromodomain helicase DNA-binding domain (CHD) protein family includes nine members (CHD 1–9), which all contain two N-terminal chromodomains, a helicase-like ATPase motif associated with nucleosome remodeling, and a less well-defined C-terminal DNA binding domain.7 As a member of the CHD family, CHD5 was identified in 2002 as a tumor suppressor gene located at 1p36 in the p19/p53 pathway.8 CHD5 is an unusual CHD member because its expression is found to be limited to the developing brain, adult brain, and adrenal gland, suggesting a role in the development or function of the neural system.9 Its role in tumorigenesis was originally demonstrated by genetic mapping studies in neuroblastomas. In 2003, Thompson et al.10 found that CHD5 maps within a small region of deletion on 1p36.3 in human neuroblastomas; they also detected low or undetectable CHD5 expression in both neuroblastoma cell lines and tissues. Subsequent cumulative research evidence supports CHD5 as a candidate tumor suppressor gene in more than half of human cancers. For example, Wang et al.11 reported that the ectopic expression of CHD5 in laryngeal cancer cells led to significant inhibition of growth and invasiveness; Zhao et al.12 detected low or absent CHD5 expression in lung cancer cell lines and tissues; in epithelial ovarian cancer, Wong et al.13 found that downregulation of CHD5 was an independent adverse prognostic factor for this tumor. These findings suggest that CHD5 deficiency is a common molecular event in human tumorigenesis.

The CHD5 gene was also found to be significantly deleted in glioma cell lines14, 15; however, its expression pattern and clinical significance in human malignant glioma remains unclear. To address this question, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured by real-time quantitative polymerase chain reaction (RT–PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors and prognosis in glioma patients was statistically analyzed.

Section snippets

Patients and tissue samples

This study was approved by the Research Ethics Committee of Tangdu Hospital, Fourth Military Medical University, China. Written informed consent was obtained from all patients. All specimens were handled and anonymized according to ethical and legal standards.

A total of 128 formalin-fixed, paraffin-embedded specimens of gliomas resected between 2000 and 2010 were retrieved from the archives of the Pathology Department of Tangdu Hospital, Fourth Military Medical University, China. All slides

CHD5 mRNA and protein expression in human glioma tissues

CHD5 mRNA expression was detected in 20 glioma and 10 non-neoplastic brain tissues normalized to GAPDH. As shown in Fig. 1A and C, we found that expression of the CHD5 gene was distinctly decreased in glioma tissues compared to non-neoplastic brain tissues, and corresponded to glioma WHO grade; expression in high-grade (III–IV, 0.2 ± 0.01) and low-grade (I–II, 0.9 ± 0.04) gliomas were both significantly lower than expression in non-neoplastic brain tissues (1.8 ± 0.06; p < 0.001 and p < 0.008,

Discussion

Human gliomas are aggressive tumors with a poor prognosis because of their heterogeneous biology, high invasiveness, rapid tumor cell proliferation, and often advanced stage at diagnosis, despite recent advances in diagnostic modalities. Several genetic and molecular mechanisms of tumorigenesis in gliomas have been described; however, many factors affecting tumor progression remain unclear. It is therefore necessary to identify molecular markers related to prognosis that could be used as

Conflicts of interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

This work was funded by National Natural Science Foundation of China (NO. 81101736, NO.81272419), Talents Supported Plan Foundation of Tangdu Hospital for Yanyang Tu (2011) and Science and Technology Innovation Foundation of Tangdu Hospital for Yanyang Tu(2012).

References (25)

  • S.K. Muthuswamy

    A new tumor suppressor that regulates tissue architecture

    PLoS Med

    (2009)
  • C. Cai et al.

    MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in vivo by targeting tumor suppressor CHD5

    PLoS ONE

    (2012)
  • Cited by (28)

    • CHROMO domain readers: A rainbow of opportunities

      2023, Chromatin Readers in Health and Disease
    • CHD5 is a potential tumor suppressor in non small cell lung cancer (NSCLC)

      2017, Gene
      Citation Excerpt :

      Upon that, its role in tumorigenesis was originally demonstrated in neuroblastoma (Bagchi et al., 2007). Subsequently its down-regulation has been associated with the development and progression of many different kinds of human malignancies (Du et al., 2016; Liu et al., 2015; Zhao et al., 2014a; Zhao et al., 2014b; Fatemi et al., 2014; Wang et al., 2013). However, there is only one study in the literature investigating the CHD5 gene in NSCLC.

    • Epigenetic dysregulation in brain tumors and neurodevelopment

      2017, Neuropsychiatric Disorders and Epigenetics
    • The tumor suppressor chromodomain helicase DNA-binding protein 5 (CHD5) remodels nucleosomes by unwrapping

      2014, Journal of Biological Chemistry
      Citation Excerpt :

      nucleosome assembly protein 1 CHD5 is also a key tumor suppressor that is frequently lost in a variety of cancers characterized by deletions of chromosome 1p36.3 (4–6). In addition to deletion, loss of CHD5 expression by promoter CpG-hypermethylation occurs in some cancers (7, 8).

    View all citing articles on Scopus
    1

    These authors contributed equally to this study.

    View full text