Abstract
Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose alpha, beta, and delta members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.
Highlights
Several human cancers are caused by a block in differentiation and accumulation of cellular precursors
To verify whether the transcriptional changes were primary events, we monitored binding of FUS-CHOP to these promoters by chromatin immunoprecipitation (ChIP) with anti-CHOP, anti-FUS, and two control antibodies: an irrelevant anti-Flag and one against the widespread CCAAT-factor NF-Y (Fig. 1D)
We investigated the molecular mechanisms underlying the activity of the anticancer drug trabectedin in Myxoid liposarcomas (MLS)/RCLS, an effort prompted by the exceedingly high antitumor activity noticed in MLS/RCLS among sarcomas [13]
Summary
Several human cancers are caused by a block in differentiation and accumulation of cellular precursors. The major liposarcoma subtypes identified by morphologic and cytogenetic criteria are (a) well differentiated/de-differentiated, (b) usual myxoid/round cell, and (c) pleomorphic [1]. >90% of usual myxoid/round cell liposarcomas (MLS/RCLS) carry a t(12;16) (q13;p11) chromosome rearrangement resulting in a fusion between the NH2terminal part of FUS and the full-length CHOP [2]. The FUS gene is constitutively active and codes for a nRNA-binding protein, whose NH2-terminal part contains an autonomous transcriptional activation domain required for the full oncogenic potential of the chimera [6]. One of the important roles of CHOP is to heterodimerize with other members of the family, serving as a dominant negative protein by altering their transcriptional potential [7]. C/EBPh and C/EBPy play redundant roles in the early phases of commitment, whereas C/EBPa becomes active and important in the later phases leading to terminal differentiation [7]
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