Histone acetyltransferase p300 and PAX3-FOXO1 fusion protein interaction interface (p300/PAX3-FOXO1 interface)

The p300 interaction interface with the PAX3-FOXO1 fusion protein is a pivotal therapeutic target in alveolar rhabdomyosarcoma (ARMS) (Gryder et al., 2017, Cancer Discovery). PAX3-FOXO1 is a chimeric transcription factor that functions as a master regulator of the ARMS oncogenic program by recruiting the histone acetyltransferase p300 (EP300) to distal enhancers (Gryder et al., 2019, Nature Genetics). This recruitment facilitates the formation of super-enhancers through extensive H3K27 acetylation, driving the high-level expression of genes essential for tumor cell survival and proliferation, such as MYCN and MYOD1 (Bharathy et al., 2018, Science Signaling). The physical interaction between the PAX3-FOXO1 transactivation domain and the p300 coactivator is essential for the fusion protein's transcriptional activity. Disrupting this interface or inhibiting the enzymatic activity of the recruited p300 can lead to the collapse of the oncogenic transcriptional network and induce myogenic differentiation or apoptosis in tumor cells. While direct small-molecule inhibitors of the protein-protein interface are in early research stages, inhibitors targeting the p300 bromodomain or acetyltransferase domain, such as A-485 or CCS1477, have shown significant preclinical efficacy in PAX3-FOXO1-positive models (Bohm et al., 2021, Cancer Research). However, the ubiquitous role of p300 in normal cellular transcription poses a challenge for achieving a therapeutic window without systemic toxicity.

Other names

EP300-PAX3-FOXO1 complexp300-PAX3-FOXO1 protein-protein interactionPAX3-FOXO1/p300 recruitment sitep300 CH1 domain interaction with PAX3-FOXO1

Disruption of the physical recruitment of p300 by the PAX3-FOXO1 fusion protein and inhibition of p300-mediated histone acetylation at oncogenic super-enhancers.