title: Regulatory mechanisms, expression levels and proliferation effects of the FUS-DDIT3 fusion oncogene in liposarcoma.
abstract: Fusion oncogenes are among the most common types of oncogene in human cancers. The gene rearrangements result in new combinations of regulatory elements and functional protein domains. Here we studied a subgroup of sarcomas and leukaemias characterized by the FET (FUS, EWSR1, TAF15) family of fusion oncogenes, including FUS-DDIT3 in myxoid liposarcoma (MLS). We investigated the regulatory mechanisms, expression levels and effects of FUS-DDIT3 in detail. FUS-DDIT3 showed a lower expression than normal FUS at both the mRNA and protein levels, and single-cell analysis revealed a lack of correlation between FUS-DDIT3 and FUS expression. FUS-DDIT3 transcription was regulated by the FUS promotor, while its mRNA stability depended on the DDIT3 sequence. FUS-DDIT3 protein stability was regulated by protein interactions through the FUS part, rather than the leucine zipper containing DDIT3 part. In addition, in vitro as well as in vivo FUS-DDIT3 protein expression data displayed highly variable expression levels between individual MLS cells. Combined mRNA and protein analyses at the single-cell level showed that FUS-DDIT3 protein expression was inversely correlated to the expression of cell proliferation-associated genes. We concluded that FUS-DDIT3 is uniquely regulated at the transcriptional as well as the post-translational level and that its expression level is important for MLS tumour development. The FET fusion oncogenes are potentially powerful drug targets and detailed knowledge about their regulation and functions may help in the development of novel treatments.
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Pierre
authors: P
authors: Åman
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Soheila
authors: S
authors: Dolatabadi
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.|Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: David
authors: D
authors: Svec
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Emma
authors: E
authors: Jonasson
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Setareh
authors: S
authors: Safavi
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Daniel
authors: D
authors: Andersson
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Pernilla
authors: P
authors: Grundevik
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Christer
authors: C
authors: Thomsen
authors: Sahlgrenska Cancer Centre, Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
authors: Anders
authors: A
authors: Ståhlberg
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; C532377:FUS-DDIT3 fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger
keywords: chimaeric transcript; fusion gene regulation; mRNA stability; myxoid liposarcoma