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Cellular and Molecular Biology

HECTD3 regulates the tumourigenesis of glioblastoma by polyubiquitinating PARP1 and activating EGFR signalling pathway

British Journal of Cancer volume 127, pages 1925–1938 (2022)Cite this article

Subjects

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.

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Fig. 1: HECTD3 is highly expressed in GBM tissues and associated with a poor prognosis.
Fig. 2: Knockdown of HECTD3 inhibited the proliferation and migration ability of GBM cells.
Fig. 3: HECTD3 is required for GBM cell proliferation.
Fig. 4: The HECTD3 DOC domain interacts with the PARP1 DNA-binding domain.
Fig. 5: Depletion of HECTD3 reduces the expression of PARP1 and induces apoptosis and DNA damage in GBM cells.
Fig. 6: HECTD3 mediates the K63-linked polyubiquitination of PARP1.
Fig. 7: HECTD3 activates the EGFR-mediated signalling pathway through PARP1.

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Data availability

All data analysed or generated in this study are included in this article as well as in the Supplementary Information file.

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Acknowledgements

We thank Daping Hospital (Chongqing, China) for providing primary glioblastoma cells (GBM-3). We thank Dr. Ulrich Aymard Ekomi Moure for correcting spelling and grammar errors. We also thank Jifu Li for providing technical support during the use of the Confocal Laser Scanning Microscope (Olympus Fv1000, Japan).

Funding

This research was supported by the Natural Science Foundation of Chongqing (cstc2022ycjh-bgzxm0145) and (cstc2019jcyjzdxmX0033).

Author information

Authors and Affiliations

  1. State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China

    Guanghui Zhang, Ruoyue Tan, Sicheng Wan, Rui Yang, Xiaosong Hu, Erhu Zhao & Hongjuan Cui

  2. Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China

    Xiangfei Ding, Jingping Zhang, Biao Li & Hongjuan Cui

  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

    Ping Liang

  4. Chongqing Key Laboratory of Pediatrics, 400014, Chongqing, China

    Ping Liang

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Contributions

GZ and HC were responsible for the design of the study. GZ, PL, RT, SW, BL, and XH performed the experiments. HC, GZ, XD, RY, and EZ analysed the data and designed the figures. GZ, PL, and JZ wrote the manuscript.

Corresponding authors

Correspondence to Ping Liang or Hongjuan Cui.

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The authors declare no competing interests.

Ethics approval and consent to participate

Animal handling was approved by the Committee for Animal Protection and ethics of Southwest University. All experiments were conducted following the Guidelines for Animal Health and Use of the Ministry of Science and Technology of China (2006). Clinical glioma tissue samples were purchased from Chaoying Biotechnology Co., Ltd, and the study was approved by the Medical Ethics Committee of Tongxu County People’s Hospital of Henan Province and all participants provided informed consent.

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Zhang, G., Tan, R., Wan, S. et al. HECTD3 regulates the tumourigenesis of glioblastoma by polyubiquitinating PARP1 and activating EGFR signalling pathway. Br J Cancer 127, 1925–1938 (2022). https://doi.org/10.1038/s41416-022-01970-9

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