Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas.

Abstract

BACKGROUND:

The checkpoint with forkhead-associated domain and RING-finger domain (CHFR) is a mitotic checkpoint protein with tumor-suppressor functions. In this study, the authors investigated the epigenetic and genetic mechanisms that regulate CHFR expression in esophageal adenocarcinomas (EACs).

METHODS:

Quantitative reverse transcriptase polymerase chain reaction analysis demonstrated downregulation of CHFR transcript in 79% of EACs (44 of 56) compared with 41 normal samples (P < .001). Immunohistochemical analysis of CHFR protein expression showed absence or weak immunostaining for CHFR in 75% of EACs (56 of 75) compared with normal tissue samples. The authors next examined the promoter DNA hypermethylation of CHFR by using quantitative bisulfite pyrosequencing technology. They detected significant CHFR promoter DNA hypermethylation in 31% of tumor samples (18 of 58) compared with normal samples (P < .001). Treatment of OE33 cells with 5-Aza-deoxycytidine led to reduction in the promoter DNA methylation levels with restoration of the CHFR mRNA expression, which confirmed promoter DNA methylation as an epigenetic mechanism regulating CHFR expression. However, they identified several EACs where the CHFR mRNA expression was silenced in the absence of notable methylation. Therefore, the authors examined the relative DNA copy number level of CHFR compared with normal samples.

RESULTS:

The results confirmed a decrease or absence of the relative CHFR DNA copy number levels in 59% of tumor samples. Nine tumors that showed loss of CHFR mRNA expression, in absence of promoter DNA hypermethylation, demonstrated a significant loss of relative CHFR DNA copy numbers.

CONCLUSIONS:

Taken together, their findings demonstrated that both epigenetic and genetic mechanisms were involved in silencing CHFR expression in EACs.

• Authors: Mohammed Soutto, Dunfa Peng, Mohammad Razvi, Petra Ruemmele, Arndt Hartmann, Albert Roessner, Regine Schneider-Stock, Wael El-Rifai
• Journal: Cancer (Cancer) Vol. 116 Issue 17 Pg. 4033-42 (Sep 01 2010) ISSN: 0008-543X [Print] United States
• PMID: 20564104 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Cancer 2010. (c) 2010 American Cancer Society.

Chemical References

• Cell Cycle Proteins
• Neoplasm Proteins
• Poly-ADP-Ribose Binding Proteins
• CHFR protein, human
• Ubiquitin-Protein Ligases

Topics

• Adenocarcinoma (genetics)
• Cell Cycle Proteins (genetics)
• DNA Methylation
• Down-Regulation
• Esophageal Neoplasms (genetics)
• Gene Dosage
• Gene Silencing
• Genes, Tumor Suppressor
• Genes, cdc
• Humans
• Immunohistochemistry
• Neoplasm Proteins (genetics)
• Poly-ADP-Ribose Binding Proteins
• Ubiquitin-Protein Ligases