Background　Acylphosphatase　2　(ACYP2)　is　involved　in　cell　differentiation,　energy　metabolism　and　hydrolysis　of　intracellular　ion　pump.　It　has　been　reported　as　a　negative　regulator　in　leukemia　and　a　positive　regulator　in　colon　cancer,　respectively.　However,　its　biological　role　in　glioma　remains　totally　unclear.　Methods　We　performed　quantitative　RT-PCR　(qRT-PCR),　immunohistochemistry　(IHC)　and　western　blot　assays　to　evaluate　ACYP2　expression.　The　functions　of　ACYP2　in　glioma　cells　were　determined　by　a　series　of　in　vitro　and　in　vivo　experiments,　including　cell　proliferation,　colony　formation,　cell　cycle,　apoptosis,　migration,　invasion　and　nude　mouse　tumorigenicity　assays.　In　addition,　western　blot　and　co-immunoprecipitation　(Co-IP)　assays　were　used　to　identify　its　downstream　targets.　Results　Knocking　down　ACYP2　in　glioma　cells　significantly　inhibited　cell　proliferation,　colony　formation,　migration,　invasion　and　tumorigenic　potential　in　nude　mice,　and　induced　cell　cycle　arrest　and　apoptosis.　Conversely,　ectopic　expression　of　ACYP2　in　glioma　cells　dramatically　promoted　malignant　phenotypes　of　glioma　cells.　Mechanistically,　ACYP2　promoted　malignant　progression　of　glioma　cells　through　regulating　intracellular　Ca(2+)homeostasis　via　its　interaction　with　PMCA4,　thereby　activating　c-Myc　and　PTP1B/STAT3　signals.　This　could　be　effectively　reversed　by　Ca(2+)chelator　BAPTA-AM　or　calpain　inhibitor　calpeptin.　Conclusions　Our　data　demonstrate　that　ACYP2　functions　as　an　oncogene　in　glioma　through　activating　c-Myc　and　STAT3　signals　via　the　regulation　of　intracellular　Ca(2+)homeostasis,　and　indicate　that　ACYP2　may　be　a　potential　therapeutic　target　and　prognostic　biomarker　in　gliomas.