Myxoid liposarcoma (MLPS) is a malignant adipogenic neoplasm that is characterised by the translocation t(12;16)(q13;11). This translocation results in the fusion of the transactivating domain of a DNA/RNA binding protein, FUS, and the transcription factor, DDIT3. There is strong evidence that the translocation is the primary oncogenic event in MLPS and that it acts as an aberrant transcription factor.
To identify genes regulated by FUS-DDIT3, we used siRNAs to knockdown gene expression of both FUS and DDIT3 in the MLPS cell line, 402-91 followed by transcriptional profiling. Knockdown of FUS and DDIT3 resulted in 8 genes differentially regulated by 24h and 39 genes differentially regulated at 48h compared to controls, with more than twice as many genes being down-regulated than up-regulated. The genes identified in this study were compared with genes differentially expressed between MLPS and other tumours in a gene expression profiling study including 138 bone and soft tissue tumours.
One strong candidate identified to be regulated by FUS-DDIT3 was SRY (sox determining region Y)-box 11, SOX11. SOX11 is a member of the group C SOX transcription factors and plays a role in embryonic development, determination of cell fate and neurogenesis. SOX11 was downregulated after FUS-DDIT3 knockdown in the 402-91 cell line (p-value = 6.51x10-6) and conversely upregulated in MLPS primary tumours compared to other bone and soft tissue tumours (log-fold change of 5.47, p-value = 5.69x10-7). The strong upregulation of SOX11 in primary tumours may be driven directly by FUS-DDIT3. Furthermore, 2 of the genes downregulated at 48h after FUS-DDIT3 knockdown and upregulated in primary MLPS have been shown to be direct targets of SOX11. SOX11 and its downstream targets may play a specific role in the development of MLPS and functional studies are currently underway to investigate the role of SOX11 in this cancer.