Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. .
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