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CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma

Oncogene volume 41, pages 4524–4536 (2022)Cite this article

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Abstract

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. Therapeutic targeting of osteosarcoma has been unsuccessful; therefore, identifying novel osteosarcoma pathogenesis could offer new therapeutic options. CDK7 is a subunit within the general transcription factor TFIIH. We aim to explore the new mechanism by which CDK7 regulates osteosarcoma and our studies may provide new theoretical support for the use of CDK7 inhibitors in the treatment of osteosarcoma. Here, we investigate the molecular mechanism underlying the association between CDK7 and GRP78 in osteosarcoma. Specifically, we find that an E3 ubiquitin ligase TRIM21 binds and targets GRP78 for ubiquitination and degradation, whereas CDK7 phosphorylates GRP78 at T69 to inhibit TRIM21 recruitment, leading to GRP78 stabilization. Notably, a CDK7-specific inhibitor, THZ1, blunts osteosarcoma growth and metastasis. Combination treatment with CDK7 and GRP78 inhibitors yield additive effects on osteosarcoma growth and progression inhibition. Thus, simultaneous suppression of CDK7 and GRP78 activity represents a potential new approach for the treatment of osteosarcoma. In conclusion, the discovery of this previously unknown CDK7/GRP78 signaling axis provides the molecular basis and the rationale to target human osteosarcoma.

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Fig. 1: CDK7 is essential for tumor growth and progression in osteosarcoma.
Fig. 2: CDK7 interacts with GRP78 and phosphorylates GRP78 at Thr 69 site.
Fig. 3: CDK7-dependent GRP78 Thr69 phosphorylation blocks the degradation of GRP78.
Fig. 4: TRIM21 mediates the polyubiquitylation and degradation of GRP78.
Fig. 5: GRP78 promotes osteosarcoma growth and metastasis.
Fig. 6: Pharmacological inhibition of CDK7/GRP78 and effectively reduces tumor burden.
Fig. 7: A proposed model for both function and regulation of CDK7/GRP78 signaling axis in osteosarcoma.

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Acknowledgements

We thank all members of Shanghai Bone Tumor Institute for their assistance.

Funding

This work was supported by NSFC (81874124); Shanghai Science and Technology Committee Rising-Star Program (19QA1407200).

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  1. These authors contributed equally: Tao Zhang, Jingjie Li.

Authors and Affiliations

  1. Department of Orthopedics, Shanghai Bone Tumor Institution, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P. R. China

    Tao Zhang, Mengkai Yang, Xinglong Ma, Zhuoying Wang, Xiaojun Ma, Mengxiong Sun, Wei Sun, Jing Xu, Yingqi Hua & Zhengdong Cai

  2. Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P. R. China

    Jingjie Li

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Contributions

TZ, JJL, MKY, and XLM designed and conducted experiments, analyzed data and wrote the paper; ZYW, XJM, MXS, WS and JX provided reagents, technical and data analysis assistance; TZ, YQH, and ZDC conceived and supervised the project, designed experiments, and analyzed data. All authors approved the final version of the manuscript.

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Correspondence to Tao Zhang, Yingqi Hua or Zhengdong Cai.

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Zhang, T., Li, J., Yang, M. et al. CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma. Oncogene 41, 4524–4536 (2022). https://doi.org/10.1038/s41388-022-02446-z

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