Qu Yi, Gharbi Naouel, Yuan Xing, Olsen Jan Roger, Blicher Pernille, Dalhus Bjørn, Brokstad Karl A, Lin Biaoyang, Øyan Anne Margrete, Zhang Weidong, Kalland Karl-Henning, Ke Xisong
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Microbiology, Haukeland University Hospital, N-5021 Bergen, Norway;
Institute of Marine Biology, University of Bergen, N-5020 Bergen, Norway;
Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9339-44. doi: 10.1073/pnas.1604520113. Epub 2016 Aug 1.
Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.
Wnt（无翅型）/β-连环蛋白信号通路的致癌性突变在主要癌症类型中经常被观察到。然而，到目前为止，尚无针对Wnt/β-连环蛋白信号传导的治疗药物可用于临床。在此，我们证明了阿昔替尼，一种临床批准的药物，可显著阻断癌细胞、斑马鱼和Apc（min/+）小鼠中的Wnt/β-连环蛋白信号传导。值得注意的是，阿昔替尼通过促进核β-连环蛋白的降解，独立于GSK3β（糖原合酶激酶3β）/APC（腺瘤性息肉病结肠）复合物，显著诱导癌细胞中的Wnt不对称性和非随机DNA分离。使用与二维差异凝胶电泳（2D-DIGE）和质谱联用的药物亲和反应性靶标稳定性（DARTS）分析，我们确定了E3泛素连接酶SHPRH（含SNF2、组蛋白连接体、PHD和RING指结构域的解旋酶）是阿昔替尼阻断Wnt/β-连环蛋白信号传导的直接靶标。用阿昔替尼治疗可稳定SHPRH，从而增加β-连环蛋白的泛素化和降解。我们的研究结果提示了一种以前未报道的核β-连环蛋白调节机制，并表明阿昔替尼，一种临床批准的药物，将为核β-连环蛋白异常激活的癌症患者提供治疗益处。
