CHD8 is an independent prognostic indicator that regulates Wnt/β-catenin signaling and the cell cycle in gastric cancer.

The chromodomain helicase DNA-binding (CHD) family comprises a class of chromatin remodeling enzymes. Previous studies suggest that CHD8 may negatively regulate various genes and signaling pathways, such as the Wnt/β‑catenin pathway. However, few studies have investigated the role of CHD8 in cancer cells. We analyzed the expression of CHD8 in cancer lesions and corresponding non-cancerous tissues to demonstrate the prognostic significance of CHD8 expression in 101 cases of gastric cancer. We also investigated the functional implications of aberrant CHD8 expression by conducting gene set enrichment analysis (GSEA). Expression of CHD8 mRNA was significantly lower in gastric cancer tissues compared to that in corresponding normal tissues (P=0.003). In multivariate analysis for overall survival, we found that CHD8 expression was an independent prognostic factor in gastric cancer. Moreover, GSEA revealed that CHD8 was significantly associated with genes involved in the Wnt/β‑catenin pathway and in the cell cycle. In addition, knockdown of CHD8 expression in the gastric cancer cell lines, MKN45 and NUGC4, promoted proliferation. In conclusion, the present study suggests that loss of CHD8 expression may be a novel indicator for biological aggressiveness in gastric cancer.

[1]  Keiichi I. Nakayama,et al.  Histone H1 Recruitment by CHD8 Is Essential for Suppression of the Wnt–β-Catenin Signaling Pathway , 2011, Molecular and Cellular Biology.

[2]  Meng Chen,et al.  Regulation of serum response factor activity and smooth muscle cell apoptosis by chromodomain helicase DNA-binding protein 8. , 2010, American journal of physiology. Cell physiology.

[3]  Tushar Menon,et al.  Regulation of androgen-responsive transcription by the chromatin remodeling factor CHD8. , 2010, Molecular endocrinology.

[4]  Joel A. Yates,et al.  Regulation of HOXA2 gene expression by the ATP‐dependent chromatin remodeling enzyme CHD8 , 2010, FEBS letters.

[5]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[6]  Hyun Cheol Chung,et al.  Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer , 2009, PLoS genetics.

[7]  M. Esteller,et al.  The chromatin remodeling factor CHD8 interacts with elongating RNA polymerase II and controls expression of the cyclin E2 gene , 2009, Nucleic acids research.

[8]  K. Nakayama,et al.  CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis , 2009, Nature Cell Biology.

[9]  Brandi A. Thompson,et al.  CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes , 2008, Molecular and Cellular Biology.

[10]  M. Washburn,et al.  CHD8 Associates with Human Staf and Contributes to Efficient U6 RNA Polymerase III Transcription , 2007, Molecular and Cellular Biology.

[11]  P. Georgel,et al.  CHD proteins: a diverse family with strong ties. , 2007, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[12]  A. Imbalzano,et al.  The Chd family of chromatin remodelers. , 2007, Mutation research.

[13]  H. Vogel,et al.  CHD5 Is a Tumor Suppressor at Human 1p36 , 2007, Cell.

[14]  K. Jones,et al.  Wnt signaling: is the party in the nucleus? , 2006, Genes & development.

[15]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[16]  R. Nusse,et al.  Convergence of Wnt, ß-Catenin, and Cadherin Pathways , 2004, Science.

[17]  James T Kadonaga,et al.  Chromatin remodeling by ATP-dependent molecular machines. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[18]  T. Tsukiyama.  The in vivo functions of ATP-dependent chromatin-remodelling factors , 2002, Nature Reviews Molecular Cell Biology.

[19]  A. Fukui,et al.  A Novel β-Catenin-binding Protein Inhibits β-Catenin-dependent Tcf Activation and Axis Formation* , 2000, The Journal of Biological Chemistry.

[20]  H. Clevers,et al.  Linking Colorectal Cancer to Wnt Signaling , 2000, Cell.

[21]  A. Jemal,et al.  Cancer Statistics, 2004 , 2004, CA: a cancer journal for clinicians.