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The FUS-DDIT3 interactome in myxoid liposarcoma Yu, Jamie Simin Emma


Myxoid liposarcoma is a malignant fatty tumour that develops in the deep soft tissue. While local control rates are good, current chemotherapy options remain ineffective against metastatic disease. Myxoid liposarcoma is characterized by a balanced translocation involving FUS (12q13) and DDIT3 (16p11). The resulting FUS-DDIT3 oncoprotein is proposed to function as an aberrant transcription factor but its exact mechanism of action has remained unclear, rendering it difficult to formulate rational strategies for targeted therapy. A current gap in knowledge behind the oncogenic functions of FUS-DDIT3 is the lack of comprehensive data on its interactome, which could identify the oncoprotein's key partners. This study utilized immunoprecipitation-mass spectrometry to identify the FUS-DDIT3 interactome in whole cell lysates of myxoid liposarcoma cells, and results showed an enrichment of RNA processing proteins. RNA-seq analysis was performed on myxoid liposarcoma cells after FUS-DDIT3 knockdown to look for changes in the alternative splicing profile, but no evidence of such changes was seen. Further TMT-labeled immunoprecipitation-mass spectrometry analyses in nuclear lysates of myxoid liposarcoma cells showed that members of several chromatin regulatory complexes were present in the FUS-DDIT3 interactome. These complexes included the NuRD, SWI/SNF, PRC1, PRC2 and MLL1 COMPASS-like complexes. Co-immunoprecipitation experiments validated the association of FUS-DDIT3 with BRG1/SMARCA4, BAF155/SMARCC1, BAF57/SMARCE1, HDAC2, KDM1A, and MTA1. Knockdown of FUS-DDIT3 also reduced H3K27ac levels at the promoter of a gene target, PTX3. Other sarcoma fusion oncoproteins have been reported to interact with chromatin regulators and affect histone modifications or chromatin remodeling as one of their oncogenic mechanisms. Data from this study suggests that FUS-DDIT3 may utilize a similar epigenetic mechanism of action, providing potential candidates for targeted therapy as epigenetic aberrations are potentially reversible by existing and emerging epigenetic drugs.

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