SYT-SSX is critical for cyclin D1 expression in synovial sarcoma cells: a gain of function of the t(X;18)(p11.2;q11.2) translocation

Cancer Res. 2002 Jul 1;62(13):3861-7.

Abstract

The SYT-SSX fusion gene has been implicated in the malignant tumor cell growth of synovial sarcoma, but the underlying molecular mechanisms are still poorly understood. Here we demonstrate that SYT-SSX is critical for the protein level of cyclin D1 in synovial sarcoma cells. Antisense oligonucleotides to SYT-SSX mRNA rapidly and drastically decreased cyclin D1 and subsequently inhibited cell growth. This effect is specific for SYT-SSX, without involving the wild-type genes SYT or SSX. The decrease in cyclin D1 expression, which occurred shortly after inhibition of SYT-SSX expression, was found to be primarily dependent on an increased degradation of the cyclin D1 protein, as assessed by pulse-chase experiments using [(35)S]methionine. Furthermore, transfection of mouse fibroblasts with SYT-SSX cDNA increased the stability of cyclin D1. Because treatment with a proteasome inhibitor restored cyclin D1 expression, it seems like SYT-SSX interferes with ubiquitin-dependent degradation of cyclin D1. However, SYT-SSX-regulated cyclin D1 expression was proven to be independent of the glycogen synthetase kinase-3beta pathway. Taken together, our study provides evidence that SYT-SSX stabilizes cyclin D1 and is critical for cyclin D1 expression in synovial sarcoma cells. SYT-SSX-dependent expression of cyclin D1 may be an important mechanism in the development and progression of synovial sarcoma and also raises the possibility for targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Division / physiology
  • Chromosomes, Human, Pair 18*
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / metabolism
  • Down-Regulation
  • Humans
  • Mice
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Sarcoma, Synovial / genetics*
  • Sarcoma, Synovial / metabolism
  • Sarcoma, Synovial / pathology
  • Transfection
  • Translocation, Genetic*
  • Tumor Cells, Cultured
  • X Chromosome*

Substances

  • Oligonucleotides, Antisense
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • SYT-SSX fusion protein
  • Cyclin D1
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt