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CBX3 accelerates the malignant progression of glioblastoma multiforme by stabilizing EGFR expression

Oncogene volume 41, pages 3051–3063 (2022)Cite this article

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Abstract

CBX3, also known as HP1γ, is a major isoform of heterochromatin protein 1, whose deregulation has been reported to promote the development of human cancers. However, the molecular mechanism of CBX3 in glioblastoma multiforme (GBM) are unclear. Our study reported the identification of CBX3 as a potential therapeutic target for GBM. Briefly, we found that, CBX3 is significantly upregulated in GBM and reduces patient survival. In addition, functional assays demonstrated that CBX3 significantly promote the proliferation, invasion and tumorigenesis of GBM cells in vitro and in vivo. Mechanistically, Erlotinib, a small molecule targeting epidermal growth factor receptor (EGFR) tyrosine kinase, was used to demonstrate that CBX3 direct the malignant progression of GBM are EGFR dependent. Previous studies have shown that PARK2(Parkin) and STUB1(Carboxy Terminus of Hsp70-Interacting Protein) are EGFR-specific E3 ligases. Notably, we verified that CBX3 directly suppressed PARK2 and STUB1 at the transcriptional level through its CD domain to reduce the ubiquitination of EGFR. Moreover, the CSD domain of CBX3 interacted with PARK2 and regulated its ubiquitination to further reduce its protein level. Collectively, these results revealed an unknown mechanism underlying the pathogenesis of GBM and confirmed that CBX3 is a promising therapeutic target.

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Fig. 1: High expression of CBX3 is an indicator of poor prognosis in patients with GBM.
Fig. 2: CBX3 is essential for the proliferation, tumor growth and invasion of GBM cells.
Fig. 3: CBX3 reduces the ubiquitination of EGFR to mediate the EGFR signaling pathway.
Fig. 4: CBX3 directly inhibits STUB1 and PARK2 through its CD domain.
Fig. 5: CBX3 regulates the stability of PARK2 through its CSD domain.
Fig. 6: PARK2 and STUB1 act as downstream targets of CBX3 to regulate the progression of GBM.

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Acknowledgements

We are grateful for the research platform provided by Southwest University, and thank all the participants who contributed to this work.

Funding

This research was supported by the Natural Science Foundation of Chongqing (cstc2019jcyj-zdxmX0033) and Chongqing Doctoral Research and Innovation Project (CYB21131).

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Authors and Affiliations

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

    Wen Peng, Hanghua Liang, Jianbin Hou, Xiaosong Hu, Feng Wang, Jiayi Zhang, Shengjun Geng & Hongjuan Cui

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

    Wen Peng, Hanghua Liang, Jianbin Hou, Xiaosong Hu, Feng Wang, Jiayi Zhang, Shengjun Geng & Hongjuan Cui

  3. Department of Neurosurgery, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Shuang Shi, Jiacheng Zhong, Xiaochuan Sun & Dong Zhong

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Contributions

HC, DZ, and WP designed this study. WP and HC performed all the experimental work. WP, SS, JZ, HL, JH, XH, JZ, SG, FW, XS, DZ, and HC analyzed the experimental data. HC and WP wrote drafts of the main text and collated diagrams. All authors have read, revised, and approved the final manuscript.

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Correspondence to Dong Zhong or Hongjuan Cui.

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Peng, W., Shi, S., Zhong, J. et al. CBX3 accelerates the malignant progression of glioblastoma multiforme by stabilizing EGFR expression. Oncogene 41, 3051–3063 (2022). https://doi.org/10.1038/s41388-022-02296-9

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