FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor,Cancer Discovery

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FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-02-01 , DOI: 10.1158/2159-8290.cd-17-0468
Leili Ran ₁ , Yuedan Chen _{1,

2} , Jessica Sher ₁ , Elissa W.P. Wong ₁ , Devan Murphy ₁ , Jenny Q. Zhang ₁ , Dan Li ₁ , Kemal Deniz ₃ , Inna Sirota ₄ , Zhen Cao _{1,

2} , Shangqian Wang ₁ , Youxin Guan ₁ , Shipra Shukla ₁ , Katie Yang Li ₅ , Alan Chramiec _{5,

6} , Yuanyuan Xie ₁ , Deyou Zheng _{7,

8,

9} , Richard P. Koche ₅ , Cristina R. Antonescu ₁₀ , Yu Chen _{1,

2,

11,

12} , Ping Chi _{1,

2,

11,

12}

Affiliation

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.
3Department of Pathology, Erciyes University, Kayseri, Turkey.
4Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
5Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
6Biomedical Engineering, Columbia University, New York, New York.
7Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.
8Department of Neurology, Albert Einstein College of Medicine, Bronx, New York.
9Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
10Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
11Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
12Department of Medicine, Weill Cornell Medical College, New York, New York.

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

中文翻译：

FOXF1定义了胃肠道间质肿瘤的核心调控电路

整合上游信号传导和下游核反应的细胞环境决定了不同癌症类型的致癌行为并决定了治疗反应。在这里，我们发现在胃肠道间质瘤（GIST）中，叉头家族成员FOXF1直接控制两个主要调节因子KIT和ETV1的转录，都是Cajal谱系规范的GIST前体-间质细胞和GIST肿瘤发生所必需的。此外，FOXF1与ETV1在增强子上共定位，并作为先驱因子通过调节局部染色质环境（包括染色质可及性，增强子维持和ETV1结合）来调节ETV1依赖性GIST谱系特异性转录组。在功能上，FOXF1是人类GIST细胞体外生长和鼠GIST肿瘤体内生长和维持所必需的。上游信号和核反应的同时控制建立了独特的调控模式，并突出了FOXF1在实施GIST细胞环境以实现高度谱系限制的临床行为和治疗反应中的关键作用。

参见Lee和Duensing的相关评论，第1页。146。

本文在本期功能中突出显示。127

更新日期：2018-02-05

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