This study demonstrates for the first time a crucial role of DNA-PK/MYT1L interplay in transcriptional regulation of CXCR1, highlighting the regulatory role of the neuron-specific transcription factor MYT1L in a proliferative signaling loop involving CXC chemokine ligand 1 (CXCL1, also known as GROα) and IL-8/CXCR1 in glioblastoma that may represent a pharmacological target loop for therapeutic intervention for this disease. Here, CXCR1 is linked to glioblastoma.