This study reveals a positive feedback DNA-PK/MYT1L-CXCR1 proliferative signaling loop that contributes to the progression of glioblastoma via the ERK1/2 pathway and provides a novel insight into the role of DNA-PK in the MYT1L-mediated transactivation of CXCR1. Here, PRKDC is linked to glioblastoma.