1. ¹Laboratory of Molecular Medicine, Human Genome Center, The University of Tokyo, Tokyo, Japan
2. ²Division of Clinical Genome Research, The University of Tokyo, Tokyo, Japan
3. ³Division of Gene Expression and Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
4. ⁴Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan

Correspondence: Assistant Professor K Matsuda, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, Japan. E-mail: koichima@ims.u-tokyo.ac.jp

Received 21 October 2008; Revised 11 March 2009; Accepted 12 May 2009; Published online 22 June 2009.

Abstract

Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.