Tan Ying, Li Qiu-Meng, Huang Ning, Cheng Si, Zhao Guan-Jian, Chen Hong, Chen Song, Tang Zhao-Hua, Zhang Wen-Qian, Huang Qin, Cheng Yuan
Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cell Death Dis. 2017 Aug 10;8(8):e2981. doi: 10.1038/cddis.2017.385.
DACT2, one of the Dact gene family members, was shown to function as a tumor suppressor. However, its function in gliomas remains largely unknown. In this study, we investigated the role of DACT2, underlying molecular mechanisms and its clinical significance in glioma patients. Downexpression of DACT2 in gliomas compared with adjacent normal brain tissues was correlated with glioma grade and poor survival. Cox regression analysis revealed that the DACT2 is an independent prognostic indicator for glioma patients. Overexpression of DACT2 in glioma cells inhibited proliferation, cell cycle and enhanced apoptosis, sensitivity to temozolomide in vitro and suppressed tumor growth in vivo. Whereas knockdown of DACT2 induce opposite reaction. Mechanistically, overexpression of DACT2 resulted in upregulation of important signaling molecules such as p-YAP and p-β-catenin, and prevent YAP translocating into nucleus and sequestering in the cytoplasm to degrade. The study further proved that DACT2 can suppress YAP through Wnt/β-catenin signaling pathway. Collectively, these data indicate that DACT2 has a tumor suppressor function via inactivation of YAP pathway, providing a promising target for the treatment of gliomas.
DACT2是Dact基因家族成员之一，已被证明具有肿瘤抑制功能。然而，其在胶质瘤中的作用仍 largely unknown。在本研究中，我们调查了DACT2在胶质瘤患者中的作用、潜在分子机制及其临床意义。与相邻正常脑组织相比，胶质瘤中DACT2的低表达与胶质瘤分级和不良生存相关。Cox回归分析显示，DACT2是胶质瘤患者的独立预后指标。在胶质瘤细胞中过表达DACT2可抑制增殖、细胞周期并增强凋亡、体外对替莫唑胺的敏感性，并在体内抑制肿瘤生长。而敲低DACT2则诱导相反的反应。机制上，DACT2的过表达导致重要信号分子如p-YAP和p-β-连环蛋白上调，并阻止YAP转运到细胞核中并在细胞质中滞留以降解。该研究进一步证明DACT2可通过Wnt/β-连环蛋白信号通路抑制YAP。总体而言，这些数据表明DACT2通过YAP通路失活具有肿瘤抑制功能，为胶质瘤治疗提供了一个有前景的靶点。
