Cell Reports: Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma (Chen, Houghton, & Shiio Labs)

• Kruthi Suvarna
• Panneerselvam Jayabal
• Xiuye Ma
• Hu Wang
• Yidong Chen
• Susan T. Weintraub
• Xianlin Han
• Peter J. Houghton
• Yuzuru Shiio 8

Highlights

Ewing sarcoma depends on secreted SMPD1, a ceramide-generating enzyme, and ceramide GPR64 responds to ceramide and mediates critical growth signaling in Ewing sarcoma Ceramide induces the cleavage of the C-terminal intracellular domain (ICD) of GPR64 GPR64 ICD restrains the protein levels of RIF1 via a SPOP-dependent mechanism

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.

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