HNF1B-mediated repression of SLUG is suppressed by EZH2 in aggressive prostate cancer
HNF1B-mediated repression of SLUG is suppressed by EZH2 in aggressive prostate cancer
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在侵袭性前列腺癌中，EZH2 抑制 HNF1B 介导的 SLUG 抑制
DOI：
10.1038/s41388-019-1065-2
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Lan, Fei
中科院分区：
文献类型：
--
作者：
Wang, Jianqing;He, Chenxi;Lan, Fei
前列腺癌是发达国家男性最常见的恶性肿瘤。zeste增强子同源物2（EZH 2），主要的组蛋白H3赖氨酸27甲基转移酶的过表达，已连接到前列腺癌恶性。然而，其下游基因和途径尚未得到很好的建立。在这里，我们显示肿瘤抑制因子肝细胞核因子1 β（HNF 1B）作为EZH 2的直接下游靶点。EZH 2结合HNF 1B基因座并抑制前列腺癌细胞系中HNF 1B的表达，这进一步得到了临床样品中EZH 2和HNF 1B表达之间的反向相关性的支持。一致地，恢复的HNF 1B表达显著抑制EZH 2介导的过度生长和EMT过程，包括前列腺癌细胞系的迁移和侵袭。从机制上讲，我们发现HNF 1B主要结合数千个靶基因的启动子，并差异调节876个基因的表达。我们还鉴定了RBBP 7/RbAP 46作为HNF 1B相互作用蛋白，其是HNF 1B介导的SLUG表达抑制和EMT过程所需的。更重要的是，我们发现HNF 1B的表达越高，单独或与EZH 2的表达越低，前列腺癌的预后越好。综上所述，我们已经在前列腺癌中建立了以前被低估的EZH 2-HNF 1B-SLUG轴，并且还提供了支持HNF 1B作为转移性前列腺癌的潜在预后标志物的证据。
Prostate cancer is the most common malignancy in men in developed countries. Overexpression of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 methyltransferase, has been connected to prostate cancer malignancy. However, its downstream genes and pathways have not been well established. Here, we show tumor suppressor Hepatocyte Nuclear Factor 1 beta (HNF1B) as a direct downstream target of EZH2. EZH2 binds HNF1B locus and suppresses HNF1B expression in prostate cancer cell lines, which is further supported by the reverse correlation between EZH2 and HNF1B expression in clinical samples. Consistently, restored HNF1B expression significantly suppresses EZH2-mediated overgrowth and EMT processes, including migration and invasion of prostate cancer cell lines. Mechanistically, we find that HNF1B primarily binds the promoters of thousands of target genes, and differentially regulates the expression of 876 genes. We also identify RBBP7/RbAP46 as a HNF1B interacting protein which is required for HNF1B-mediated repression of SLUG expression and EMT process. Importantly, we find that higher HNF1B expression strongly predicts better prognosis of prostate cancer, alone or together with lower EZH2 expression. Taken together, we have established a previously underappreciated axis of EZH2-HNF1B-SLUG in prostate cancer, and also provide evidence supporting HNF1B as a potential prognosis marker for metastatic prostate cancer.