Ajuba inhibits hepatocellular carcinoma cell growth via targeting of β-catenin and YAP signaling and is regulated by E3 ligase Hakai through neddylation

• DOI: 10.1186/s13046-018-0806-3
• Publication Date: 2018-07-24T03:55:34Z
• Authors: Min Liu; Ke Jiang; Guibin Lin; Peng Liu; Yumei Yan; Tian Ye; Gang Yao; Martin P. Barr; Dapeng Liang; Yang Wang; Peng Gong; Songshu Meng; Haozhe Piao
• Keywords: 0301 basic medicine; Carcinoma, Hepatocellular; Hakai; β-Catenin; Hepatocellular carcinoma; Research; Ubiquitin-Protein Ligases; Liver Neoplasms; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Mice, Nude; LIM Domain Proteins; Transfection; Mice; 03 medical and health sciences; Cell Line, Tumor; Ajuba; Animals; Humans; YAP; Neddylation; RC254-282; beta Catenin

Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain Ajuba regulates YAP is implicated in tumorigenesis. However, roles mechanism expression HCC cells remain unclear. E3 ligase Hakai shown to interact other family members whether interacts unknown. cell lines stably depleted or were established using lentiviruses expressing shRNAs against Hakai. effects on determined by a number cell-based analyses including anchorage-independent growth, three dimension cultures trans-well invasion assay. In vivo tumor growth was xenograft model sections examined immunohistochemistry. Co-immunoprecipitation, confocal microscopy immunoblot assay used examine the interaction between Depletion significantly enhanced invasion, formation spheroids model, suggesting suppressor function for HCC. Mechanistically, depletion triggered E-cadherin loss translocation increased Cyclin D1 levels. addition, upregulated levels its target gene CYR61. Furthermore, siRNA-mediated knockdown either attenuated pro-tumor cells. Notably, stability regulated Hakai, an E-cadherin. interacted via HYB induced neddylation, which antagonized neddylation inhibitor, MLN4924, but not MG132. We further show that overexpression markedly spheroid-formation ability xenografts whereas resulted these opposite effects, indicating oncogenic role also D1. Our data suggest HCC, uncover underlying regulation stability.