FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma

Frontiers in Oncology

Anders Ståhlberg¹  Tobias Österlund¹  Soheila Dolatabadi²  Pierre Åman²  Lisa Andersson²  Emma Jonasson²  Malin Lindén²  Manuel Luna Santamaría³ 

[1]Region Västra Götaland, Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden

[2]Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

[3]Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

关键词: cancer stem cells;    CD44;    FET sarcomas;    FUS-DDIT3;    JAK-STAT signaling;    myxoid liposarcoma;   

DOI  :  10.3389/fonc.2022.816894

来源: DOAJ

【 摘 要 】

Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.

【 授权许可】

Unknown