Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array

Abstract

Homozygous deletions (HD) provide an important resource for identifying the location of candidate tumor suppressor genes. To identify the tumor suppressor gene in oral cancer, we employed high-resolution comparative genomic hybridization (CGH)-array analysis. We identified a homozygous loss of FAT (4q35), a new member of the human cadherin superfamily, from genome-wide screening of copy number alterations in one primary oral cancer. This result was evaluated by genomic polymerase chain reaction in 13 oral cancer cell lines and 20 primary oral cancers and Southern blot in the cell lines. We found frequent exonic HD of FAT in the cell lines (3/13, 23%) and in primary oral cancers (16/20, 80%). FAT expression was absent in these cell lines. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). Moreover, loss of gene expression was identified in other types of squamous cell carcinoma. The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Our results identify mutations in FAT as an important factor in the development of oral cancer and indicate the importance of FATs function in some squamous cell carcinomas.

Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

“…Significantly, mammalian homologs of each component of the Drosophila Hippo-LATS pathway have been identified [Fat4 for Fat, Merlin for Merlin, Ex for Ex, RASSF1A for dRASSF, hWW45 for Sav, Mst1 and Mst2 for Hippo, LATS1 and LATS2 for LATS, MOB1 (Msp1 one binder) for Mats, and YAP (Yesassociated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) for Yorkie] (12). We and others recently showed that part of the Hippo-LATS signaling pathway discovered in Drosophila are conserved in mammals and that many members of the pathway could be confirmed as either tumor suppressors (Fat4, Merlin, RASSF1A, Mst1/2, LATS1/2, MOB1) or oncogenes (YAP and TAZ) in human cancers (15)(16)(17)(18)(19). Therefore, further characterization of Hippo-LATS pathway and its regulators in mammals will have great implication for not only our understanding the molecular mechanism of tumorigenesis, but also for future targeting of this pathway for cancer therapies.…”

Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

“…FAT1 was previously suggested to be a tumor suppressor gene in human (8). Nevertheless, the current study revealed the expression of FAT1 in most of the OSCC cases and cell lines.…”

“…FAT1 is considered to be a tumor suppressor gene based on the evidence in Drosophila and the results of CGH studies (1,(7)(8)(9). In addition, FAT1 indirectly regulates cell proliferation; Hou et al demonstrated that the inhibition of FAT1 expression promotes cell proliferation whereas the overexpression of FAT1 suppresses proliferation in vascular muscle cells (10).…”

“…The human OSCC cell lines (HSC2, HSC3, HSC4, OSC2, SAS, B88, kB, SCC9, SCC25, SCC66 and SCC111) (8,17) were maintained in Dulbecco's modified Eagle's medium (DMEM) (wako) supplemented with 10% fetal bovine serum (FBS; Biosource, Camarillo, CA), 100 u/ml penicillin, and 100 µg/ml streptomycin (Invitrogen, Carlsbad, CA), and incubated in a humidified atmosphere of 95% air and 5% CO 2 at 37˚C.…”

Dual Processing of FAT1 Cadherin Protein by Human Melanoma Cells Generates Distinct Protein Products

“…There are also data to suggest that this shared functionality between Drosophila FAT and FAT1 may extend to a suppressor function for human FAT1. In a study designed to identify the location of candidate tumor suppressor genes in oral cancer, homozygous deletions of FAT1 were identified in a genome-wide screening of a primary oral cancer (12). Further analysis by genomic PCR revealed that 80% of 20 primary oral cancers exhibited exonic homozygous deletions of FAT1.…”