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Carcinogenesis Advance Access originally published online on February 17, 2008
Carcinogenesis 2008 29(3):629-637; doi:10.1093/carcin/bgm291
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion

Mirang Kim1,8, Hay-Ran Jang1, Jeong-Hwan Kim1, Seung-Moo Noh2, Kyu-Sang Song3, June-Sik Cho4, Hyun-Yong Jeong5, Jim C. Norman6, Patrick T. Caswell6, Gyeong Hoon Kang7, Seon-Young Kim1, Hyang-Sook Yoo1 and Yong Sung Kim1,8,*

1 Medical Genomics Research Center, KRIBB, Daejeon 305-806, Korea
2 Department of General Surgery
3 Department of Pathology
4 Department of Diagnostic Radiology and
5 Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Korea
6 Integrin Cell Biology Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
7 Department of Pathology, Seoul National University College of Medicine, Seoul 110-744, Korea
8 Department of Functional Genomics, University of Science and Technology, Daejeon 305-806, Korea

* To whom correspondence should be addressed. Tel: +82 42 879 8110; Fax: +82 42 879 8119; Email: yongsung{at}kribb.re.kr

Protein kinase D (PKD) 1 influences cell migration by mediating both trans-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of PKD1 was aberrantly methylated in gastric cancer cell lines. Silencing of PKD1 expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of PKD1. Treatment with 5-aza-2'-deoxycytidine and trichostatin A partially reversed PKD1 methylation and restored gene expression in PKD1-silenced cell lines. Real-time reverse transcription–polymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in PKD1 expression compared with each normal-appearing tissue and that this downregulation of PKD1 expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of PKD1 in aging, normal-appearing mucosal tissues, suggesting that PKD1 methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that PKD1 is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.

Abbreviations: 5-aza-dC, 5-aza-2'-deoxycytidine; ChIP, chromatin immunoprecipitation; LOE, loss of expression; PCR, polymerase chain reaction; PKD, protein kinase D; RLGS, restriction landmark genomic scanning; RT, reverse transcription; siRNA, small interfering RNA; TSA, trichostatin A

Received September 3, 2007; revised November 27, 2007; accepted November 27, 2007.


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