Systematic Interrogation of CBP/p300 Dependency in Cancer

Abstract

CBP and p300 are closely related paralogs that function as versatile transcriptional co-activator proteins. These paralogs function as histone acetyltransferases (HATs) and mediate canonical signaling programs by acetylating histone H3 lysines 18 and 27 (H3K18ac; H3K27ac) at regulatory elements such as promoters and enhancers. These genomic loci play critical roles in the context of cancer and are essential to maintain oncogenic transcription. Therefore, the p300/CBP HATs are attractive targets for disrupting epigenetically regulated oncogenic transcription programs. Several inhibitors of p300/CBP HATs have been reported, with A-485 being one of the best-characterized. A-485 has been shown to selectively inhibit cell proliferation across lineage-specific tumor types, suggesting the potential of therapeutically targeting p300 and CBP in cancer. However, the landscape of sensitivities to p300/CBP inhibition or deletion in cancer remain unknown, and a clear biomarker of p300/CBP dependency is lacking. To address this, we systematically functionalized the impact of p300 and CBP knock-out individually and in combination across hundreds of human cancer cell models (PRISM) to unbiasedly identify oncogenic contexts that confer p300/CBP dependency. We have identified a subset of 37 cell lines genetically dependent on the double knockout of p300/CBP (log2fc 2 std). We found that the dependent cell lines were not enriched in a particular lineage and had no associated biomarker. Additionally, complementary inhibitor (A-485) screens identified a lack of correlation between p300/CBP genetic dependency and inhibitor sensitivity. Finally, we report p300 and CBP are selectively required for the expression of JUN, a proto-oncogene part of the AP-1 transcription factor complex, in the p300/CBP dependent cell lines but not in the non-dependent lines. This suggests a potential mechanism where p300/CBP dependent cancer cell lines are vulnerable to p300/CBP loss through the loss of c-Jun.