ABSTRACT
Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not ß-catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking ß-catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation.
Subject(s)
Gene Expression Profiling/methods , Oncogene Proteins, Fusion/genetics , Transcription Factors/genetics , Wnt Signaling Pathway/genetics , Animals , Axin Protein/genetics , Axin Protein/metabolism , Blotting, Western , Cell Line , Cell Line, Tumor , Co-Repressor Proteins , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Humans , Mice , Microscopy, Confocal , Oncogene Proteins, Fusion/metabolism , RNA Interference , Repressor Proteins/genetics , Repressor Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sarcoma, Synovial/genetics , Sarcoma, Synovial/metabolism , Sarcoma, Synovial/pathology , TCF Transcription Factors/genetics , TCF Transcription Factors/metabolism , Transcription Factors/metabolism , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
We have recently demonstrated that human pediatric mesenchymal stem cells can be reprogrammed toward a Ewing sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSCs is shared by embryonic stem cells and CSCs from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSCs is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor maintenance may depend on deregulation of TARBP2-dependent miRNA expression.
