Nrf1 Is Endowed with a Dominant Tumor-Repressing Effect onto the Wnt/ β -Catenin-Dependent and Wnt/ β -Catenin-Independent Signaling Networks in the Human Liver Cancer

作者：Jiayu Chen, Meng Wang, Yuancai Xiang, Xufang Ru, Yonggang Ren, Xiping Liu, Lu Qiu, Yiguo Zhang · 发表于：Oxidative Medicine and Cellular Longevity · 年份：2020 · DOI：10.1155/2020/5138539 · 被引用次数：21 · 研究领域：Genomics, phytochemicals, and oxidative stress、Kruppel-like factors research、Wnt/β-catenin signaling in development and cancer

Our previous work revealed that Nrf1 α exerts a tumor-repressing effect because its genomic loss (to yield Nrf1α -/- ) results in oncogenic activation of Nrf2 and target genes. Interestingly, β -catenin is concurrently activated by loss of Nrf1 α in a way similar to β -catenin-driven liver tumor. However, a presumable relationship between Nrf1 and β -catenin is not yet established. Here, we demonstrate that Nrf1 enhanced ubiquitination of β -catenin for targeting proteasomal degradation. Conversely, knockdown of Nrf1 by its short hairpin RNA (shNrf1) caused accumulation of β -catenin so as to translocate the nucleus, allowing activation of a subset of Wnt/ β -catenin signaling responsive genes, which leads to the epithelial-mesenchymal transition (EMT) and related cellular processes. Such silencing of Nrf1 resulted in malgrowth of human hepatocellular carcinoma, along with malignant invasion and metastasis to the lung and liver in xenograft model mice. Further transcriptomic sequencing unraveled significant differences in the expression of both Wnt/ β -catenin-dependent and Wnt/ β -catenin-independent responsive genes implicated in the cell process, shape, and behavior of the shNrf1-expressing tumor. Notably, we identified that β -catenin is not a target gene of Nrf1, but this CNC-bZIP factor contributes to differential or opposing expression of other critical genes, such as CDH1 , Wnt5A , Wnt11A , FZD10 , LEF1 , TCF4 , SMAD4 , MMP9 , PTEN , PI3K , JUN , and p53 , each of whi...