Open AccessKIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer
Author(s) -
Kee-Beom Kim,
Ashish Kabra,
Dong-Wook Kim,
Yongming Xue,
Yuesheng Huang,
Pei-Chi Hou,
Yunpeng Zhou,
Leilani J Miranda,
Jae-Il Park,
Xiaobing Shi,
Timothy P. Bender,
John H. Bushweller,
Kwon-Sik Park
Publication year - 2022
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abl4618
Subject(s) - biology , cancer research , carcinogenesis , creb binding protein , transcription factor , microbiology and biotechnology , cancer , genetics , gene , creb
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, completeEp300 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.