Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan.
Department of Surgery, IMSUT Hospital, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan.
Oncogene. 2019 Aug;38(32):6051-6064. doi: 10.1038/s41388-019-0856-9. Epub 2019 Jul 10.
Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the β-catenin/TCF7L2 complex. Although genes upregulated by Wnt/β-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/β-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/β-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/β-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/β-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.
Wnt 信号通路的损伤在结直肠癌的发展中起着关键作用，通过激活β-连环蛋白/TCF7L2 复合物。虽然已经对受 Wnt/β-连环蛋白信号上调的基因进行了深入研究，但对下调基因的作用知之甚少。以前，我们报道干扰素诱导的具有四肽重复结构域 2（IFIT2）的蛋白质受 Wnt/β-连环蛋白信号的下调，IFIT2 的表达受抑制赋予结直肠癌（CRC）细胞抗凋亡特性。然而，Wnt/β-连环蛋白信号调节 IFIT2 的机制仍有待阐明。在这项研究中，我们发现 IFIT2 的表达受 IRF1 诱导，而 IRF1 受 Wnt/β-连环蛋白信号的负调控。此外，我们发现 IRF1 的下调是通过其通过泛素化蛋白酶体途径进行降解介导的，并且包含 USP1 和 UAF1 的去泛素酶复合物的活性降低参与了 Wnt/β-连环蛋白信号对 IRF1 的降解。这些数据应该为更好地理解 Wnt 信号通路和人类癌变提供依据。
