The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to establish organoids in vitro, but blocked the ability to recover from treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss-of-heterozygosity of the tumor suppressor gene Apc . The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with differentially expressed genes between the two models. Oct1 ChIPseq using HCT116 colon carcinoma cells identifies target genes associated with mitotic stability, metabolism, stress response and malignancy. This set of gene targets overlaps significantly with genes differentially expressed in the two tumor models. These results reveal that Oct1 is selectively required for recovery after colon damage, and that Oct1 has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology. Author summary Colorectal cancer is the second leading cause of cancer death in the United States. Approximately 35% of diagnosed patients eventually succumb to disease. The high incidence and mortality due to colon cancer demand a better understanding of factors controlling the physiology and pathophysiology of the gastrointestinal tract. Previously, we and others showed that the widely expressed transcription factor Oct1 is expressed at higher protein levels in stem cells, including intestinal stem cells. Here we use deletion of a conditional mouse Oct1 ( Pou2f1 ) allele in two different intestinal stem cell compartments to study gut homeostasis. We then proceed to investigate the effect of Oct1 loss in colon regeneration and malignancy. The results indicate that Oct1 loss is dispensable for maintenance of the mouse gut, but required for recovery after damage to the colon epithelium. We also find that Oct1 loss has opposing effects in two different mouse colon cancer models, and further that the two models are associated with different gene expression signatures. The differentially expressed genes are enriched for Oct1 targets, suggesting that differential gene control by Oct1 is one mechanism underlying the different outcomes.
【초록키워드】 Treatment, stem cells, Tumor, Gene Expression, Mortality, Stress, sodium, Cancer, in vitro, outcome, metabolism, outcomes, Colorectal cancer, Colorectal, stability, Characteristics, pathophysiology, Physiology, Patient, death, Deletion, stress response, targets, organoids, United States, incidence, etiology, in vivo, disease, Differentially expressed genes, mechanism, gastrointestinal tract, homeostasis, differentially expressed gene, Target genes, Organoid, Gut, malignancy, maintenance, Colon cancer, stem cell, transcription factor, target gene, tumor suppressor gene, colon carcinoma, sulfate, Intestinal stem cells, Colon, Factor, dextran, overlap, damage, passage, allele, protein level, intestinal stem cell, ChIPseq, Pou2f1, sodium sulfate, Suppressor gene, tumor suppressor, Effect, The United States, Cell, gene target, identify, blocked, significantly, diagnosed, required, determine, expressed, promote, maintain, deleted, driven by, differentially expressed, mitotic, gut stem cell, preserved, proceed, 【제목키워드】 regulate, required,