The WD repeat domain 5 (WDR5), also known as SWD3 and BIG-3, is often overexpressed in cancers, however its molecular function in cancer remains to be elucidated. In this study, we found that WDR5 promoted the proliferation and self-renewal of glioblastoma and neuroblastoma cells. The data from databases and Western blot assay showed that CARM1 is a downstream gene of WDR5-Myc axis. In addition, we observed that WDR5 promoted the binding of Myc to CARM1 promoter by interacting with Myc and inducing histone 3 lysine 4 trimethylation (H3K4me3). Dual luciferase reporter system indicated that Myc binds to the upstream region (-520 to -515) before transcription start site (TSS) of CARM1 promoter. These findings suggest a novel regulatory model for the proliferation and tumorigenesis of glioblastoma and neuroblastoma by WDR5-Myc axis. (C) 2020 Elsevier Inc. All rights reserved.