FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor

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 ChenPing Chi

Research output: Contribution to journalArticle

12 Scopus citations

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 defi nes 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.

Original languageEnglish (US)
Pages (from-to)234-251
Number of pages18
JournalCancer Discovery
Volume8
Issue number2
DOIs
StatePublished - Feb 1 2018

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ASJC Scopus subject areas

  • Oncology

Cite this

Ran, L., Chen, Y., Sher, J., Wong, E. W. P., Murphy, D., Zhang, J. Q., Li, D., Deniz, K., Sirota, I., Cao, Z., Wang, S., Guan, Y., Shukla, S., Li, K. Y., Chramiec, A., Xie, Y., Zheng, D., Koche, R. P., Antonescu, C. R., ... Chi, P. (2018). FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor. Cancer Discovery, 8(2), 234-251. https://doi.org/10.1158/2159-8290.CD-17-0468