American Association for Cancer Research
15417786mcr180289-sup-199058_3_supp_4900393_pc0sl6.pdf (165.83 kB)

Supplemental Figure 5 from USP6 Confers Sensitivity to IFN-Mediated Apoptosis through Modulation of TRAIL Signaling in Ewing Sarcoma

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journal contribution
posted on 2023-04-03, 16:26 authored by Ian C. Henrich, Robert Young, Laura Quick, Andre M. Oliveira, Margaret M. Chou

Apoptotic pathways overview and controls for CRISPR and inhibitors






Ewing sarcoma is the second most common sarcoma of the bone, afflicting predominantly the pediatric population. Although patients with localized disease exhibit favorable survival rates, patients with metastatic disease suffer a dismal 5-year rate of approximately 25%. Thus, there is a great need to develop treatments to combat the disseminated disease. Ubiquitin-specific protease 6 (USP6/TRE17) has been implicated as the key etiologic factor in several benign mesenchymal tumors, including nodular fasciitis and aneurysmal bone cyst (ABC). However, the role of USP6 in the biology of malignant entities remains unexplored. Previously, it was observed that USP6 is sufficient to drive formation of tumors mimicking ABC and nodular fasciitis, and that it functions through JAK1/STAT3 signaling. However, in the context of Ewing sarcoma, USP6 does not enhance the transformation, but rather triggers an IFN response signature, both in cultured Ewing sarcoma cells in vitro and in clinical specimens in vivo. Not only does USP6 independently induce activation of the IFN signaling mediators, JAK1 and STAT1, but it also renders Ewing sarcoma cells exquisitely responsive to exogenous IFNs, potentiating activation of STAT1 and STAT3. Furthermore, IFNβ (a type I IFN) induces apoptosis specifically in USP6-positive but not USP6-negative Ewing sarcoma cells. Finally, apoptosis is mediated through the proapoptotic ligand TRAIL, which is synergistically induced by type I IFN and USP6. These findings provide the first insights into USP6 functions in a clinically relevant malignant entity, and raise the possibility of using IFN for targeting USP6-positive Ewing sarcoma.

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