FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor

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Ran L., Chen Y., Sher J., Wong E. W. P., Murphy D., Zhang J. Q., ...Daha Fazla

CANCER DISCOVERY, cilt.8, sa.2, ss.234-251, 2018 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 8 Sayı: 2
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1158/2159-8290.cd-17-0468
  • Dergi Adı: CANCER DISCOVERY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.234-251
  • Erciyes Üniversitesi Adresli: Evet

Özet

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.