G-protein Coupled Receptor GPR17 Inhibits Glioma Development By Increasing PRC1-mediated ROS Production

Glioma is the most common primary tumor of the central nervous system.It is characterized by strong invasion ability and rapid postoperative recurrence.The overall curative effect of glioma is poor and the fatality rate is very high.The survival time of glioma patients after diagnosis is usually less than 15 months.However,the development of glioma and effective therapeutic strategies remain elusive.Here,we identify GPR17 as a potential target to treat glioma.Data mining with human LGG and GBM samples reveals that GPR17 is negatively correlated with glioma development.Overexpressing GPR17 inhibits glioma cell proliferation and induces apoptosis by raising ROS levels.GPR 17-overexpressing glioma cells are less tumorigenic in the brain than wild-type cells.Mechanistically,GPR17 inhibits the transcription of RNF2,a key component in the PRC1 complex,through cAMP/PKA/NF-κB signaling,leading to reduced histone H2A monoubiquitination.ChIP-Seq and RNA-Seq analyses identify KLF9 as a direct target of RNF2.KLF9 mediated the functions of GPR 17 and RNF2 in glioma cells.Furthermore,activation of GPR17 by its agonist inhibits glioma formation.Our findings have thus identified GPR1 7 as a key regulator of glioma development and a potential therapeutic target for gliomas.