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luminal epithelial cells inhibited those cells’ normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation.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.
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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