title: XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway.
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.
authors: Laboratory of Molecular Medicine, Human Genome Center, The University of Tokyo, Tokyo, Japan.
authors: C
authors: C
authors: Tanikawa
authors: Y
authors: Y
authors: Furukawa
authors: N
authors: N
authors: Yoshida
authors: H
authors: H
authors: Arakawa
authors: Y
authors: Y
authors: Nakamura
authors: K
authors: K
authors: Matsuda
mesh_terms: D023102:Anoikis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D053340:Xedar Receptor / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
chemical_list: C506011:EDA2R protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D053340:Xedar Receptor; D019014:fas Receptor; D051416:Focal Adhesion Protein-Tyrosine Kinases