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Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-β signaling

Oncogene volume 41, pages 2597–2608 (2022)Cite this article

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Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor as one of the deadliest cancers. The TGF-β signaling acts as an oncogenic factor in GBM, and plays vital roles in development of GBM. SMAD7 is a major inhibitor of TGF-β signaling, while the deubiquitination of SMAD7 has been poorly studied in GBM. Here, we found USP2 as a new prominent candidate that could regulate SMAD7 stability. USP2 was lost in GBM, leading to the poor prognosis in patients. Moreover, aberrant DNA methylation mediated by DNMT3A induced the low expression of USP2 in GBM. USP2 depletion induced TGF-β signaling and progression of GBM. In contrast, overexpressed USP2 suppressed TGF-β signaling and GBM development. Specifically, USP2 interacted with SMAD7 and prevented SMAD7 ubiquitination. USP2 directly cleaved Lys27- and Lys48-linked poly-ubiquitin chains of SMAD7, and Lys27-linked poly-ubiquitin chains of SMAD7 K185 mediated the recruitment of SMAD7 to HERC3, which regulated Lys63-linked poly-ubiquitination of SMAD7. Moreover, we demonstrated that the DNMT3A inhibitor SGI-1027 induced USP2, suppressed TGF-β signaling and GBM development. Thus, USP2 repressed development of GBM by inhibition TGF-β signaling pathway via the deubiquitination of SMAD7.

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Fig. 1: DNMT3A-mediated aberrant DNA methylation induced low expression of USP2 in GBM.
Fig. 2: USP2 suppressed TGF-β signaling and development of GBM.
Fig. 3: USP2 interacted with SMAD7 and regulated SMAD7 stability.
Fig. 4: USP2 deubiquitinated SMAD7 and directly cleaved Lys 27-, Lys 48-polyubiquitin chain.
Fig. 5: USP2 cleaved K27-poly-ubiquitin chain on SMAD7 K185 and further reduced the recruitment of SMAD7 to HERC3.
Fig. 6: Pharmacological increasing USP2 suppressed TGF-β signaling and development of GBM.
Fig. 7: USP2 positive correlated with SMAD7 protein in human specimens.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82120108018 and 81972153), China Postdoctoral Science Foundation (2021M701495), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, Grant No. JX10231803), and Gusu School, Nanjing Medical University (GSKY202201010).

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Author notes

  1. These authors contributed equally: Yiming Tu, Lei Xu, Jia Xu.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Yiming Tu, Lei Xu, Jia Xu, Zhongyuan Bao, Wei Tian, Yangfan Ye, Guangchi Sun, Zong Miao, Honglu Chao, Yongping You, Ning Liu & Jing Ji

  2. Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Yongping You & Jing Ji

  3. Gusu School, Nanjing Medical University, Suzhou, China

    Jing Ji

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Contributions

JJ designed the experiments. YT, LX, and JX performed the experiments. ZB, WT, YY, and GS analyzed the data. ZM and HC collected samples. YY and NL supervised the study. YT wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Jing Ji.

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Tu, Y., Xu, L., Xu, J. et al. Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-β signaling. Oncogene 41, 2597–2608 (2022). https://doi.org/10.1038/s41388-022-02275-0

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