HECTD3 通过多泛素化 PARP1 和激活 EGFR 信号通路调节胶质母细胞瘤的肿瘤发生。
HECTD3 regulates the tumourigenesis of glioblastoma by polyubiquitinating PARP1 and activating EGFR signalling pathway.
机构信息
State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
出版信息
Br J Cancer. 2022 Nov;127(11):1925-1938. doi: 10.1038/s41416-022-01970-9. Epub 2022 Sep 10.
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.
背景
E3 泛素连接酶 HECTD3 是 E6 相关蛋白羧基末端的同源物，在生物过程和肿瘤发生中发挥着关键作用。然而，HECTD3 在神经胶质瘤中的功能特征仍然难以捉摸。
方法
通过对人类神经胶质瘤数据库中的 HECTD3 分子模式分析，并在小鼠模型中进行皮下和原位注射肿瘤，来确定 HECTD3 在神经胶质瘤中的功能作用。
结果
本研究报告称，HECTD3 的 DOC 结构域与 PARP1 的 DNA 结合结构域相互作用，HECTD3 介导了 PARP1 的 K63 连接多泛素化，并稳定了后者的表达。此外，HECTD3 的半胱氨酸（Cys）823（泛素结合位点）突变显著降低了 PARP1 的多泛素化，HECTD3 参与了将泛素相关分子募集到 PARP1 泛素结合位点（分别为赖氨酸 209 和 221）。最后，HECTD3 通过激活 EGFR 介导的信号通路来调节 PARP1 的多泛素化。
结论
我们的研究结果揭示了 HECTD3 在神经胶质瘤中的潜在作用，并强烈建议进一步研究并考虑将 HECTD3 作为神经胶质瘤治疗的有前途的治疗标志物。
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