The SYT-SSX Fusion Protein Down-Regulates the Cell Proliferation Regulator COM1 in t(x;18) Synovial Sarcoma

Abstract

Chromosomal translocations are frequently associated with soft-tissue sarcomas. Fusion proteins generated by such translocations often play critical roles in tumorigenesis. Therefore, it is important to understand the function of the fusion protein to develop therapeutic interventions. The t(X;18)(p11.2;q11.2) translocation found in synovial sarcomas results in a fusion between the SYT gene on chromosome 18 and an SSX gene on the X chromosome. Although SYT-SSX fusion proteins appear to trigger synovial sarcoma development, little is known about the downstream targets of SYT-SSX. We found that the SYT-SSX fusion protein produces a dominant-negative function for SYT, which is a transcriptional coactivator. We then analyzed the gene expression profiles of SYT-SSX1-expressing HeLa cells using oligonucleotide microarrays and found that the SYT-SSX1 fusion protein directly down-regulated the expression of COM1, a regulator of cell proliferation. COM1 was found to be expressed at relatively low levels in synovial sarcoma tissues and cell lines. We then investigated the impact of conditional COM1 expression in the synovial sarcoma cell line. Increased COM1 expression resulted in induced apoptosis and in reduced cell growth and colony formation activity. Our results suggested that restoration of COM1 expression may be of therapeutic benefit in synovial sarcoma.

SUPPLEMENTAL MATERIAL

We thank Teruhiko Yoshida (NCCRI, Japan), Shinya Tanaka (Hokkaido Univ, Japan), Akira Kawai (NCCH, Japan), Susumu Hirose (NIG, Japan), and Toyomasa Katagiri (Tokyo Univ, Japan) for valuable suggestions. We also thank Rie Ito, Yoko Kitajima, and Reiko Odagawa (NCCRI, Japan) for technical support.

This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan; a grant from the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio); and a grant from the program for promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research, Ministry of Education, Culture, Sports, Science, and Technology, Japan.