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.

EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

“…With the advent of sensitive single‐cell gene expression analysis methods, it is becoming increasingly clear that stochastic variation in oncogene expression levels exist between individual cells of a tumor. This was recently demonstrated for FUS‐DDIT3 positive myxoid liposarcoma and discussed for EF in ES at the 2nd European Ewing Sarcoma Research Summit . Here, such stochastic variations in EF expression may translate into differential metastatic behavior, since EF‐low cells were demonstrated to have drastically increased migratory and metastatic potential .…”

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

“…MLS is genetically characterized by a reciprocal translocation t(12;16)(q13;p11), generating a fusion product of FUS and DDIT3. The chimeric fusion oncoprotein acts as an aberrant transcription factor and is known to influence the expression of several genes, including inhibition of adipogenic transcription factors C/EBPα and PPARγ [2], [3].…”

Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma

“…The expression of the oncogene FUS-CHOP is believed to be involved in myxoid liposarcoma tumor initiation [8]. Approximately 50% of myxoid liposarcoma cells express nuclear FUS-CHOP [9], and cells that are negative for CHOP express high levels of proliferation markers [10]. This inverse relationship between proliferation and FUS-CHOP expression results in a population of senescent cells [10].…”

“…Approximately 50% of myxoid liposarcoma cells express nuclear FUS-CHOP [9], and cells that are negative for CHOP express high levels of proliferation markers [10]. This inverse relationship between proliferation and FUS-CHOP expression results in a population of senescent cells [10]. Senescence results in apoptosis and necrosis, which is common in many tumors.…”