MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma.

The oncoprotein MYCN drives malignancy in various cancer types, including neuroblastoma (NB). However, our understanding of the mechanisms underlying its transcriptional activity and oncogenic function, as well as effective strategies to target it, remains limited. We discovered that MYCN interacts with the transcriptional coactivator KAT2A, and this interaction significantly contributes to MYCN's activity in NB. Our genome-wide analyses indicate MYCN recruits KAT2A to bind to DNA, thereby transcriptionally regulating genes associated with ribosome biogenesis and RNA processing. Moreover, we identified that MYCN directly activates KAT2A transcription, while KAT2A acetylates MYCN, increasing MYCN protein stability. Consequently, MYCN and KAT2A establish a feedforward loop that effectively regulates global gene expression, governing the malignant NB phenotype. Treatment of NB cells with a KAT2A Proteolysis Targeting Chimera (PROTAC) degrader reduces MYCN protein levels, antagonizes MYCN-mediated gene transcription regulation and suppresses cell proliferation. This study highlights the potential of transcriptional cofactors as viable targets for developing anti-MYCN therapies.