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PRDM5 Identified as a Target of Epigenetic Silencing in Colorectal and Gastric Cancer

Authors' Affiliations: ¹ Department of Molecular Biology, Cancer Research Institute, ² First Department of Internal Medicine, ³ Department of Public Health, and ⁴ Department of Oral Surgery, Sapporo Medical University, Sapporo, Japan; ⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; ⁶ PRESTO, JST, Japan, Kawaguchi, Japan; and ⁷ Division of Molecular Oncology, Aichi Cancer Center, Nagoya, Japan

Requests for reprints: Minoru Toyota, First Department of Internal Medicine, Sapporo Medical University, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan. Phone: 81-11-611-2111, ext. 3211; Fax: 81-11-618-3313; E-mail: mtoyota{at}sapmed.ac.jp.

Purpose: PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products that play key roles during cell differentiation and malignant transformation. The aim of the present study was to begin to examine the involvement of epigenetic alteration of PRDM expression in gastric and colorectal cancer.

Experimental Design: We used real-time PCR to assess expression of PRDM1-17. In addition, we used bisulfite PCR to assess DNA methylation and chromatin immunoprecipitation to assess histone modification in colorectal and gastric cancer cell lines lacking PRDM5 expression.

Results: Among the 17 PRDM family genes tested, we found that PRDM5 is the most frequently silenced in colorectal and gastric cancer cell lines. Silencing of PRDM5 was mediated by either DNA methylation or trimethylation of Lys²⁷ of histone H3. Introduction of PRDM5 into cancer cells suppressed cell growth, suggesting that it acts as a tumor suppressor in gastrointestinal cancers. Methylation of PRDM5 was detected in 6.6% (4 of 61) of primary colorectal and 50.0% (39 of 78) of primary gastric cancers but not in noncancerous tissue samples collected from areas adjacent to the tumors.

Conclusions: Our data suggest that epigenetic alteration of PRDM5 (e.g., methylation of its 5'-CpG island or trimethylation of Lys²⁷ of histone H3) likely plays a key role in the progression of gastrointestinal cancers and may be a useful molecular marker.