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Review
. 2024 Oct 14;14(10):1297.
doi: 10.3390/biom14101297.

FUS::DDIT3 Fusion Protein in the Development of Myxoid Liposarcoma and Possible Implications for Therapy

Xutong Hou  1 , Wenjin Shi  1 , Wenxin Luo  1 , Yuwen Luo  1 , Xuelin Huang  1 , Jing Li  1 , Ning Ji  1 , Qianming Chen  1
Affiliations
Review

FUS::DDIT3 Fusion Protein in the Development of Myxoid Liposarcoma and Possible Implications for Therapy

Xutong Hou et al. Biomolecules. .

Abstract

The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases and is a crucial protein in its development. Many studies have explored the role of FUS::DDIT3 in MLS, and the prevailing view is that FUS::DDIT3 inhibits adipocyte differentiation and promotes MLS growth and invasive migration by functioning as an aberrant transcription factor that affects gene expression and regulates its downstream molecules. As fusion proteins are gradually showing their potential as targets for precision cancer therapy, FUS::DDIT3 has also been investigated as a therapeutic target. Drugs that target FUS::DDIT3 and its downstream molecules for treating MLS are widely utilized in both clinical practice and experimental studies, and some of them have demonstrated promising results. This article reviews the findings of relevant research, providing an overview of the oncogenic mechanisms of the FUS::DDIT3 fusion protein in MLS, as well as recent advancements in its therapy.

Keywords: FUS::DDIT3 fusion protein; chromosomal translocation; myxoid liposarcoma.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The FUS::DDIT3 fusion protein. (A) The chromosomal translocation t (12;16) (q13;p11) that cause the FUS::DDIT3 fusion gene; (B) structure and domains of FUS, DDIT3, and FUS::DDIT3 (Type1). The RNA-binding domain of the FUS protein is replaced by DDIT3 in MLS. The FUS::DDIT3 fusion variant type1 retains the SYGQ-rich and RGG1 domains of FUS and also includes the in-frame amino acid sequence of a portion of the previously untranslated region (UTR) from DDIT3 exon2. Abbreviations: SYGQ-rich: serine–tyrosine–glycine–glutamine-rich domain; RGG: arginine–glycine–glycine box; RRM: RNA recognition motif; Znf: zinc finger; PY: proline–tyrosine nuclear localization signal; NLS: nuclear localization signal; bZIP domain: basic leucine zipper; BR: basic region; LZ: leucine zipper.
Figure 2
Figure 2
FUS::DDIT3 inhibits adipogenesis. (A) Normal mesenchymal stem cells differentiation program and relative regulation of adipogenic factors. C/EBPβ and C/EBPδ regulate the expression of PPARγ and C/EBPα. PPARγ activates the promoter of the gene encoding C/EBPα and vice versa, creating a positive feedback loop. (B) FUS::DDIT3 blocks adipogenesis via the three main signal pathways: (i) inhibiting PPARγ and C/EBPα translation; (ii) preventing the combination of C/EBPβ homodimers and BAF complex; (iii) FUS::DDIT3 co-localizes and physically binds to YAP1 and TEAD in the nucleus, and together they drive IGF2 expression, leading to an IGF-II/IGF-IR transactivation loop.
Figure 3
Figure 3
FUS::DDIT3 promotes MLS growth. FUS::DDIT3 is involved in IGF-IR/PI3K/AKT and JAK/STAT signaling pathways, miR-486/CDK4 axis, and IL-24 expression to promote MLS growth.
Figure 4
Figure 4
FUS::DDIT3 promotes MLS metastasis. The mechanisms by which FUS::DDIT3 promotes MLS metastasis include increasing the expression of matrix metalloproteinases, activating the SRC/FAK/RHO/ROCK signaling axis, and inducing the expression of PAI-1 by inhibiting the expression of miR-486.
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This work was supported by the Key Project of the Science and Technology Department of Sichuan Province (2022YFS0003), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004).

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