Dissecting Super-enhancer driven Transcriptional Dependencies Reveals Novel Oncogenes and Therapeutic Strategies of Group 3 Subtype Medulloblastoma [ChIP-seq]

Medulloblastoma (MB) is the most common malignant pediatric brain tumor and group 3 subtype (G3-MB) exhibits the worst prognosis. Dissecting super-enhancer (SE) driven transcriptional dependencies of cancer has been shown to facilitate identifying novel oncogenic mechanisms and therapeutic targets or strategies. In this study, our integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB revealed their partially conserved SE-associated transcripts were enriched of subtype-specific tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized master TFs and eleven newly identified effector oncogenes. ARL4D, one of the effector oncogenes, was further demonstrated to exert its oncogenic role via maintaining cell-cycle progression and stemness of G3-MB cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector oncogene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB. Taken together, our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic targets or strategies. To identify the super-enhancer landscape of Medulloblastoma, we performed chromatin-immunoprecipitation with sequencing (ChIP-seq) of H3K27ac antibody and RNA-seq analyses in three human primary Group 3 subtype MB cell lines (MB002, D425, HD-MB03) and SHH subtype MB (UW228). ROSE (Rank Ordering of Super-Enhancers) algorithm was used for calling SE and SE-associated genes.