Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma
Kruthi Suvarna,
Panneerselvam Jayabal,
Xiuye Ma,
Hu Wang,
Yidong Chen,
Susan T. Weintraub,
Xianlin Han,
Peter J. Houghton,
Yuzuru Shiio
Affiliations
Kruthi Suvarna
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Panneerselvam Jayabal
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Xiuye Ma
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Hu Wang
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Yidong Chen
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Population Health Sciences, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Susan T. Weintraub
Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Xianlin Han
Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Peter J. Houghton
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Yuzuru Shiio
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Corresponding author
Summary: Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.
