National Centre for Cell Science (NCCS), SP Pune University Campus, Ganeshkhind, Pune, 411007, India.
Department of Neurosurgery, King Edward Memorial Hospital, Parel, Mumbai 400 012. India.
Neoplasia. 2019 Jan;21(1):106-116. doi: 10.1016/j.neo.2018.11.005. Epub 2018 Dec 5.
Glioblastoma (GBM) is one of the most aggressive and lethal types of brain tumor. Despite the advancements in conventional or targeted therapies, median survival of GBM patients is less than 12 months. Amongst various signaling pathways aberrantly activated in glioma, active Wnt/β-catenin signaling pathway is one of the crucial oncogenic players. β-catenin, an important mediator of Wnt signaling pathway, gets phosphorylated by GSK3β complex. Phosphorylated β-catenin is specifically recognized by β-Trcp1, a F-box/WD40-repeat protein and with the help of Skp1 it plays a central role in recruiting phosphorylated β-catenin for degradation. In GBM, expression of β-TrCP1 and its affinity for β catenin is reported to be very low. Hence, we investigated whether any other members of the E3 ubiquitin ligase family could be involved in degradation of nuclear β-catenin. We here report that FBXO16, a component of SCF E3 ubiquitin ligase complex, is an interacting protein partner for β-catenin and mediates its degradation. Next, we show that FBXO16 functions as a tumor suppressor in GBM. Under normal growth conditions, FBXO16 proteasomally degrades β-catenin in a GSK-3β independent manner. Specifically, the C-terminal region of FBXO16 targets the nuclear β-catenin for degradation and inhibits TCF4/LEF1 dependent Wnt signaling pathway. The nuclear fraction of β-catenin undergoes K-48 linked poly-ubiquitination in presence of FBXO16. In summary, we show that due to low expression of FBXO16, the β-catenin is not targeted in glioma cells leading to its nuclear accumulation resulting in active Wnt signaling. Activated Wnt signaling potentiates the glioma cells toward a highly proliferative and malignant state.
胶质母细胞瘤（GBM）是最具侵袭性和致命性的脑肿瘤之一。尽管在常规或靶向治疗方面取得了进展，但 GBM 患者的中位生存期仍不到 12 个月。在胶质瘤中异常激活的各种信号通路中，活跃的 Wnt/β-catenin 信号通路是关键的致癌因子之一。β-catenin 是 Wnt 信号通路的重要介质，被 GSK3β 复合物磷酸化。磷酸化的β-catenin被β-Trcp1 特异性识别，β-Trcp1 是一种 F-box/WD40 重复蛋白，与 Skp1 一起在募集磷酸化的β-catenin进行降解中起核心作用。在 GBM 中，β-TrCP1 的表达及其与β-catenin 的亲和力报道非常低。因此，我们研究了 E3 泛素连接酶家族的其他成员是否可能参与核β-catenin 的降解。我们在此报告称，SCF E3 泛素连接酶复合物的一个组成部分 FBXO16 是β-catenin 的相互作用蛋白伴侣，并介导其降解。接下来，我们表明 FBXO16 在 GBM 中作为肿瘤抑制因子发挥作用。在正常生长条件下，FBXO16 在不依赖 GSK-3β 的情况下通过蛋白酶体降解β-catenin。具体而言，FBXO16 的 C 末端区域靶向核β-catenin 进行降解，并抑制 TCF4/LEF1 依赖性 Wnt 信号通路。在 FBXO16 的存在下，核β-catenin 经历 K-48 连接的多聚泛素化。总之，我们表明，由于 FBXO16 的低表达，β-catenin 不会在神经胶质瘤细胞中被靶向，导致其核积累，从而导致活跃的 Wnt 信号。激活的 Wnt 信号使神经胶质瘤细胞向高度增殖和恶性状态发展。
