Open AccessEWS ‐ FLI 1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma
Author(s) -
Shimizu Rikuka,
Tanaka Miwa,
Tsutsumi Shuichi,
Aburatani Hiroyuki,
Yamazaki Yukari,
Homme Mizuki,
Kitagawa Yoshimasa,
Nakamura Takuro
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13710
Subject(s) - enhancer , transcription factor , sarcoma , biology , cancer research , ewing's sarcoma , gene , gene expression , microbiology and biotechnology , genetics , medicine , pathology , chemotherapy
EWS ‐ FLI 1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS ‐ FLI 1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS ‐ FLI 1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS ‐ FLI 1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS ‐ FLI 1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS ‐ FLI 1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS ‐ FLI 1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS ‐ FLI 1. Trib1 and Nrg1 were demonstrated as target genes that are co‐regulated by EWS ‐ FLI 1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS ‐ FLI 1 function as well as the importance of GGAA microsatellites.