KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer

Kee Beom Kim, Ashish Kabra, Dong Wook Kim, Yongming Xue, Yuanjian Huang, Pei Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae Il Park, Xiaobing Shi, Timothy P. Bender, John H. Bushweller, Kwon Sik Park

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

EP300, a transcription coactivator important in proliferation and differentiation, is frequently mutated in diverse cancer types, including small cell lung cancer (SCLC). While these mutations are thought to result in loss of EP300 function, the impact on tumorigenesis remains largely unknown. Here, we demonstrate that EP300 mutants lacking acetyltransferase domain accelerate tumor development in mouse models of SCLC. However, unexpectedly, complete Ep300 knockout suppresses SCLC development and proliferation. Dissection of EP300 domains identified kinase inducible domain-interacting (KIX) domain, specifically its interaction with transcription factors including MYB, as the determinant of protumorigenic activity. Ala627 in EP300 KIX results in a higher protein-binding affinity than Asp647 at the equivalent position in CREBBP KIX, underlying the selectivity of KIX-binding partners for EP300. Blockade of KIX-mediated interactions inhibits SCLC development in mice and cell growth. This study unravels domain-specific roles for EP300 in SCLC and unique vulnerability of the EP300 KIX domain for therapeutic intervention.

Original languageEnglish
Article numbereabl4618
JournalScience advances
Volume8
Issue number7
DOIs
StatePublished - Feb 2022

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