UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis.
UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis.
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DOI：
10.1002/path.4665
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发表时间：
2016-02
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影响因子：
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通讯作者：
Costello E
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作者：
Abu-Alainin W;Gana T;Liloglou T;Olayanju A;Barrera LN;Ferguson R;Campbell F;Andrews T;Goldring C;Kitteringham N;Park BK;Nedjadi T;Schmid MC;Slupsky JR;Greenhalf W;Neoptolemos JP;Costello E
细胞防御蛋白Nrf 2是胰腺导管腺癌（PDAC）和其他癌症中肿瘤发生的介导物。然而，Nrf 2在癌症中的表达和活性的控制尚未完全了解。我们以前报道过，在大约70%的PDAC病例中，Nrf 2的关键调节因子Keap 1缺失。在这里，我们描述了一种新的机制，即表观遗传调节UHRF 1抑制Keap 1蛋白水平。在20%（5/25）的良性胰管中观察到UHRF 1表达，而在86%（114/132）的胰腺肿瘤中观察到UHRF 1表达，PDAC肿瘤（n = 124）中UHRF 1和Keap 1水平之间的负相关性明显（p = 0.002）。我们还提供了证据表明，UHRF 1介导的Nrf 2通路调节有助于PDAC的攻击行为。从PDAC细胞中去除UHRF 1会降低生长并增强凋亡和细胞周期停滞。UHRF 1耗竭还导致Nrf 2调节的下游蛋白水平降低，并伴随着氧化应激的升高，表现为谷胱甘肽水平降低和活性氧增加。同时耗竭Keap 1和UHRF 1恢复Nrf 2水平和逆转细胞周期停滞和活性氧的增加。从机制上讲，UHRF 1的缺失降低了胰腺癌细胞系中的整体和肿瘤抑制基因启动子甲基化，并且KEAP 1基因启动子甲基化在三种细胞系中的一种中降低。因此，KEAP 1基因启动子的甲基化可能有助于UHRF 1抑制Keap 1蛋白水平，尽管我们的数据表明需要探索其他机制。最后，我们证明了K-Ras驱动UHRF 1表达，建立了这种癌基因和Nrf 2介导的细胞保护之间的新联系。由于UHRF 1过表达发生在其他癌症中，其调节Keap 1-Nrf 2通路的能力可能对这些癌症的恶性行为至关重要。© 2015作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1‐mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2‐regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K‐Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2‐mediated cellular protection. Since UHRF1 over‐expression occurs in other cancers, its ability to regulate the Keap1–Nrf2 pathway may be critically important to the malignant behaviour of these cancers. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.