Guanghui Zhang1, Ruoyue Tan1, Sicheng Wan1, Rui Yang1, Xiaosong Hu1, Erhu Zhao1, Xiangfei Ding2, Jingping Zhang2, Biao Li2, Ping Liang3,4, Hongjuan Cui5,6. 1. State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China. 2. Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China. 3. Department of Neurosurgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, 400014, Chongqing, China. pingliangnet@163.com. 4. Chongqing Key Laboratory of Pediatrics, 400014, Chongqing, China. pingliangnet@163.com. 5. State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China. hongjuan.cui@gmail.com. 6. Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China. hongjuan.cui@gmail.com.
Abstract
BACKGROUND: The E3 ubiquitin ligase HECTD3 is a homologue of the E6-related protein carboxyl terminus, which plays a crucial role in biological processes and tumourigenesis. However, the functional characterisation of HECTD3 in glioblastoma is still elusive. METHODS: Determination of the functional role of HECTD3 in glioblastoma was made by a combination of HECTD3 molecular pattern analysis from human glioblastoma databases and subcutaneous and in situ injections of tumours in mice models. RESULTS: This study reports that the DOC domain of HECTD3 interacts with the DNA binding domain of PARP1, and HECTD3 mediated the K63-linked polyubiquitination of PARP1 and stabilised the latter expression. Moreover, the Cysteine (Cys) 823 (ubiquitin-binding site) mutation of HECTD3 significantly reduced PARP1 polyubiquitination and HECTD3 was involved in the recruitment of ubiquitin-related molecules to PARP1 ubiquitin-binding sites (Lysines 209 and 221, respectively). Lastly, activation of EGFR-mediated signalling pathways by HECTD3 regulates PARP1 polyubiquitination. CONCLUSION: Our results unveil the potential role of HECTD3 in glioblastoma and strongly preconise further investigation and consider HECTD3 as a promising therapeutic marker for glioblastoma treatment.
BACKGROUND: The E3 ubiquitin ligase HECTD3 is a homologue of the E6-related protein carboxyl terminus, which plays a crucial role in biological processes and tumourigenesis. However, the functional characterisation of HECTD3 in glioblastoma is still elusive. METHODS: Determination of the functional role of HECTD3 in glioblastoma was made by a combination of HECTD3 molecular pattern analysis from human glioblastoma databases and subcutaneous and in situ injections of tumours in mice models. RESULTS: This study reports that the DOC domain of HECTD3 interacts with the DNA binding domain of PARP1, and HECTD3 mediated the K63-linked polyubiquitination of PARP1 and stabilised the latter expression. Moreover, the Cysteine (Cys) 823 (ubiquitin-binding site) mutation of HECTD3 significantly reduced PARP1 polyubiquitination and HECTD3 was involved in the recruitment of ubiquitin-related molecules to PARP1 ubiquitin-binding sites (Lysines 209 and 221, respectively). Lastly, activation of EGFR-mediated signalling pathways by HECTD3 regulates PARP1 polyubiquitination. CONCLUSION: Our results unveil the potential role of HECTD3 in glioblastoma and strongly preconise further investigation and consider HECTD3 as a promising therapeutic marker for glioblastoma treatment.
Authors: M Budke; A Isla-Guerrero; C Pérez-López; M Pérez-Alvarez; A García-Grande; M J Bello; J Rey Journal: Rev Neurol Date: 2003 Nov 16-30 Impact factor: 0.870