FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor Journal Article
| Authors: | 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.; Chen, Y.; Chi, P. |
| Article Title: | FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor |
| 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. © 2017 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; treatment response; unclassified drug; human cell; nonhuman; flow cytometry; protein localization; mouse; animal tissue; gastrointestinal stromal tumor; stem cell factor receptor; interstitial cell of cajal; reverse transcription polymerase chain reaction; cell growth; cell line; animal experiment; small interfering rna; genetic transcription; carcinogenesis; genetic transfection; chromatin; chromatin immunoprecipitation; immunoblotting; tissue microarray; tumor growth; forkhead transcription factor; fluorescence activated cell sorting; transcriptome; transcription factor er81; rna isolation; human; article; cell viability assay; cell cycle assay; forkhead box f1 |
| Journal Title: | Cancer Discovery |
| Volume: | 8 |
| Issue: | 2 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-02-01 |
| Start Page: | 234 |
| End Page: | 251 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-17-0468 |
| PROVIDER: | scopus |
| PMCID: | PMC5809271 |
| PUBMED: | 29162563 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
