journal contribution
posted on 2023-04-03, 21:23 authored by Leili Ran, Yuedan Chen, Jessica Sher, Elissa W.P. Wong, Devan Murphy, Jenny Q. Zhang, Dan Li, Kemal Deniz, Inna Sirota, Zhen Cao, Shangqian Wang, Youxin Guan, Shipra Shukla, Katie Yang Li, Alan Chramiec, Yuanyuan Xie, Deyou Zheng, Richard P. Koche, Cristina R. Antonescu, Yu Chen, Ping Chi Figure S1. Expression of forkhead family transcription factors in GIST; S2. Motif analysis of the FOXF1 cistrome and validation of FOXF1 binding sites in GIST 48 cells; S3. FOXF1 regulates ETV1, KIT, and ETV1- and KIT-dependent transcriptome as well as cell cycle regulated genes; S4. Representative ChIP-seq and ATAC-seq profiles with siRNAmediated downregulation of ETV1 and FOXF1 in GIST48 cells; S5. FOXF1 regulates KIT expression and signaling; S6. FOXF1 regulates cell cycle progression and is required for growth and proliferation of GIST cells in vitro; S7. Generation of the Foxf1f-HA-Foxf1 allele; S8. Foxf1 expression in mouse GI tract and Foxf1 ablation reduces mutant Kit-mediated hyperplasia of mouse large intestine.
Funding
NCI
US DOD
Prostate Cancer Foundation
Geoffrey Beene Cancer Research Center
Gerstner Family Foundation
Bressler Scholars Fund
GIST Cancer Research Fund
Shuman Fund
GIST Cancer Awareness Fund
History
ARTICLE ABSTRACT
The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response.Significance: We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234–51. ©2017 AACR.See related commentary by Lee and Duensing, p. 146.This article is highlighted in the In This Issue feature, p. 127
