An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
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Date
2022
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W.B. Saunders
Abstract
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. © 2022
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Keywords
CD133 antigen, histone, membrane protein, prominin 1, transcription factor, transcription factor Sox9, unclassified drug, Wnt protein, PROM1 protein, human, Prom1 protein, mouse, SOX9 protein, human, Sox9 protein, mouse, adenoma, adult, animal experiment, animal model, animal tissue, Article, cancer growth, cell activity, cell proliferation, chromatin immunoprecipitation sequencing, clinical outcome, colorectal cancer, colorectal cancer cell line, colorectal carcinoma, controlled study, ectopic expression, enhancer region, epigenetics, feedback system, gene expression profiling, gene overexpression, genome-wide association study, HCC cell line (colorectal cancer), histone modification, histopathology, human, human cell, human tissue, immunohistochemistry, in vitro study, intestinal organoid, intestinal stem cell, intestine tissue, intestine tumor, intron, molecular biology, mouse, nonhuman, Paneth cell, positive feedback, protein binding, protein domain, protein expression level, protein function, regulatory mechanism, RNA sequencing, signal transduction, tissue differentiation, transcription regulation, tumor growth, upregulation, Wnt signaling, animal, cancer stem cell, cell differentiation, colorectal tumor, gene expression regulation, genetics, HT-29 cell line, metabolism, pathology, transgenic mouse, tumor cell culture, tumor suppressor gene, tumor volume, AC133 Antigen, Animals, Cell Differentiation, Cell Proliferation, Colorectal Neoplasms, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Genes, APC, HT29 Cells, Humans, Mice, Transgenic, Neoplastic Stem Cells, SOX9 Transcription Factor, Tumor Burden, Tumor Cells, Cultured, Wnt Signaling Pathway
Citation
Gastroenterology, 2022, 162, 1, pp. 209-222