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ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming
Fei Li, … , Yu Chen, Dong Gao
Fei Li, … , Yu Chen, Dong Gao
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5924-5941. https://doi.org/10.1172/JCI137967.
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Research Article Cell biology Oncology Article has an altmetric score of 3

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

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Abstract

Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells’ normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.

Authors

Fei Li, Qiuyue Yuan, Wei Di, Xinyi Xia, Zhuang Liu, Ninghui Mao, Lin Li, Chunfeng Li, Juan He, Yunguang Li, Wangxin Guo, Xiaoyu Zhang, Yiqin Zhu, Rebiguli Aji, Shangqian Wang, Xinyuan Tong, Hongbin Ji, Ping Chi, Brett Carver, Yong Wang, Yu Chen, Dong Gao

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Figure 6

ERG, not AR, is required for sustaining the luminal phenotype of prostate cancer cells in the context of Pten loss.

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ERG, not AR, is required for sustaining the luminal phenotype of prostat...
(A) ERG, Trp63, Krt8, and DAPI IF staining of Pten–/– R26ERG organoids infected with a lentiviral CRISPR/Cas9 carrying guide RNA targeting the AR (AR-KO, left) and ERG (ERG-KO, middle) and a control vector (control, right); red arrows indicate Trp63+ cells. (B) Quantification statistics for the percentage of Trp63+ cells in total cells in vitro (analyses were performed based on 9080 AR-KO cells, 8756 ERG-KO cells, and 6498 control cells, 1-way ANOVA and multiple comparisons, mean ± SEM, n = 5). (C) ERG, Trp63, Krt8, and DAPI IF staining of grafts derived from UGSM tissue recombination assays in SCID mice 8 weeks after transplantation of Pten–/– R26ERG organoids with AR-KO (top), ERG-KO (middle), and control (bottom); red arrows indicate Trp63+ cells. (D) Quantification statistics for the percentage of Trp63+ cells in total prostate cells in vivo (analyses were performed based on 3236 AR-KO cells, 2206 ERG-KO cells, and 3554 control cells, 1-way ANOVA and multiple comparisons, mean ± SEM, n = 6). (E and F) Clustering dendrogram (E) and PCA plot (F) for ERG-KO, AR-KO, and control organoids using prostate cell lineage signature genes. (G) Heatmap showing the expression of lineage-related differentially expressed genes in ERG-KO, AR-KO, and control organoids. (H and I) GSEA enrichment plot of ERG-KO versus control using ERG-downregulating basal cell signature genes (H) and ERG-upregulating luminal cell signature genes (I). Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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