By genetic inhibition of CTCF sites in ZFTA ependymoma lines, we provide evidence that insulator dysfunction is a potential oncogenic mechanism associated with transcriptional activation of the PFA tumor-dependency genes ARL4C and NELFB. Overall, our study has identified several group-specific tumor dependencies in ependymomas, opening avenues for potential therapeutic interventions that are urgently needed for this disease, especially for ZFTA and PFA ependymoma patients. Here, ARL4C is linked to neoplasm.