An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer,Gastroenterology

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An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
Gastroenterology ( IF 25.7 ) Pub Date : 2021-09-25 , DOI: 10.1053/j.gastro.2021.09.044
Xiaoyan Liang ₁ , Gina N Duronio ₂ , Yaying Yang ₃ , Pratyusha Bala ₂ , Prajna Hebbar ₄ , Sandor Spisak ₅ , Pranshu Sahgal ₆ , Harshabad Singh ₇ , Yanxi Zhang ₂ , Yingtian Xie ₅ , Paloma Cejas ₅ , Henry W Long ₅ , Adam J Bass ₈ , Nilay S Sethi ₈

Affiliation

Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China.
Department of Information Technology, National Institute of Technology Karnataka, Surathkal, India.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts; Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background and Aims

Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC.

Methods

Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing.

Results

We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell–like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 via a Wnt-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop.

Conclusions

These studies establish SOX9 as a central regulator of an enhancer-driven stem cell–like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC.

中文翻译：

由 SOX9 介导的增强子驱动的干细胞样程序可阻断结直肠癌的肠分化

背景和目标

促进干细胞活性和阻碍正常成熟的基因组改变是结直肠癌 (CRC) 发展的核心。促进这些恶性特性的关键分子介质需要进一步阐明以促进转化进展。因此，我们旨在表征阻断肠道分化的关键因素，定义其转录和表观遗传程序，并为 CRC 的治疗靶向提供临床前证据。

方法

通过组织病理学和免疫染色分析来自转基因小鼠和患者的肠组织。人类 CRC 细胞和肿瘤小鼠类器官被基因操作用于功能研究。通过 RNA 测序获得基因表达谱。使用染色质免疫沉淀测序确定组蛋白修饰和转录因子结合。

结果

我们证明 SRY-box 转录因子 9 (SOX9) 通过激活阻碍肠道分化的干细胞样程序来促进 CRC。来自小鼠模型和患者的肠腺瘤和结直肠腺癌表现出 SOX9 的异位和升高表达。功能实验表明人类 CRC 细胞系和工程肿瘤类器官需要 SOX9。破坏 SOX9 活性可通过诱导肠分化来损害原发性 CRC 肿瘤的生长。通过与全基因组增强子结合，SOX9 直接激活与 Paneth 和干细胞活性相关的基因，包括 prominin 1 ( PROM1). SOX9 通过 Wnt 响应性内含子增强子上调 PROM1。PROM1 是一种 pentaspan 跨膜蛋白，它使用其第一个细胞内结构域来支持干细胞信号传导，至少部分通过 SOX9，从而加强 PROM1-SOX9 正反馈回路。