FUS-DDIT3 prevents the development of adipocytic precursors in liposarcoma by repressing PPARgamma and C/EBPalpha and activating eIF4E.
BACKGROUND
FUS-DDIT3 is a chimeric protein generated by the most common chromosomal translocation t(12;16)(q13;p11) linked to liposarcomas, which are characterized by the accumulation of early adipocytic precursors. Current studies indicate that FUS-DDIT3- liposarcoma develops from uncommitted progenitors. However, the precise mechanism whereby FUS-DDIT3 contributes to the differentiation arrest remains to be elucidated.


RESULTS
Here we have characterized the adipocyte regulatory protein network in liposarcomas of FUS-DITT3 transgenic mice and showed that PPARgamma2 and C/EBPalpha expression was altered. Consistent with in vivo data, FUS-DDIT3 MEFs and human liposarcoma cell lines showed a similar downregulation of both PPARgamma2 and C/EBPalpha expression. Complementation studies with PPARgamma but not C/EBPalpha rescued the differentiation block in committed adipocytic precursors expressing FUS-DDIT3. Our results further show that FUS-DDIT3 interferes with the control of initiation of translation by upregulation of the eukaryotic translation initiation factors eIF2 and eIF4E both in FUS-DDIT3 mice and human liposarcomas cell lines, explaining the shift towards the truncated p30 isoform of C/EBPalpha in liposarcomas. Suppression of the FUS-DDIT3 transgene did rescue this adipocyte differentiation block. Moreover, eIF4E was also strongly upregulated in normal adipose tissue of FUS-DDIT3 transgenic mice, suggesting that overexpression of eIF4E may be a primary event in the initiation of liposarcomas. Reporter assays showed FUS-DDIT3 is involved in the upregulation of eIF4E in liposarcomas and that both domains of the fusion protein are required for affecting eIF4E expression.


CONCLUSIONS
Taken together, this study provides evidence of the molecular mechanisms involve in the disruption of normal adipocyte differentiation program in liposarcoma harbouring the chimeric gene FUS-DDIT3.
Pérez-Mancera
Pedro A
PA
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/ Universidad de Salamanca, Salamanca, Spain.
Bermejo-Rodríguez
Camino
C
Sánchez-Martín
Manuel
M
Abollo-Jiménez
Fernando
F
Pintado
Belén
B
Sánchez-García
Isidro
I
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors*; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D008080:Liposarcoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D013234:Stem Cells / Q000378:metabolism; D015854:Up-Regulation
D022763:CCAAT-Enhancer-Binding Protein-alpha; D039561:Eukaryotic Initiation Factor-4E; C532377:FUS-DDIT3 fusion protein, human; D050506:Mutant Chimeric Proteins; D015514:Oncogene Proteins, Fusion; D047495:PPAR gamma