Oncogenic Smurf1 promotes PTEN wild-type glioblastoma growth by mediating PTEN ubiquitylation

Abstract

PI3K/Akt/mTOR signaling pathway activity is highly elevated in glioblastoma (GBM). Although rapamycin is known to inhibit this pathway, GBM patients are resistant to rapamycin monotherapy. This may be related to mutations of tumor suppressor phosphatase and tensin homolog (PTEN). Here, we show that higher expression of E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) in GBM is correlated with poor prognosis. Smurf1 promotes cell growth and colony formation by accelerating cell cycle and aberrant signaling pathways. In addition, we show that Smurf1 ubiquitylates and degrades PTEN. We further demonstrate that the oncogenic role of Smurf1 is dependent on PTEN. Upregulated Smurf1 impairs PTEN activity, leading to consistent activation of PI3K/Akt/mTOR signaling pathway; and depletion of Smurf1 dramatically inhibits cell proliferation and tumor growth. Moreover, loss of Smurf1 abolishes the aberrant regulation of PTEN, causing negative feedback on PI3K/Akt/mTOR signaling pathway, and thus leading to rescue of tumor sensitivity to rapamycin in an orthotopic GBM model. Taken together, we show that Smurf1 promotes tumor progression via PTEN, and combined treatment of Smurf1 knockdown with mammalian target of rapamycin (mTOR) inhibition reduces tumor progression. These results identify a unique role of Smurf1 in mTOR inhibitor resistance and provide a strong rationale for combined therapy targeting GBM.

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Fig. 1: The role of Smurf1 is linked with PTEN in TCGA-GBM.
Fig. 2: Oncogenic effect of Smurf1 is dependent on PTEN phosphatase activity.
Fig. 3: Smurf1 interacts with and ubiquitylates PTEN.
Fig. 4: Loss of Smurf1 increases the sensitivity of tumor to rapamycin.
Fig. 5: Smurf1 knockdown resensitizes the effect of rapamycin in flank tumor.
Fig. 6: Smurf1 knockdown and rapamycin are synthetically lethal in orthotopic model.

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Acknowledgements

We thank Analysis & Testing Center, Beijing Institute of Technology and Center, School of Life Science, Beijing Institute of Technology, and Dr. Austin Cape for careful review and editing.

Funding

This work was supported by grants from Beijing Natural Science Foundation (Z190018), The Natural Science Foundation of China (81870123), China Postdoctoral Science Foundation Grant (2018M641206), and the National Science Foundation for Young Scientists of China (81902545).

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QX and HZ carried out most of the experiments. QX and HZ carried out the in vivo xenograft experiments. LD and QX designed the experiments. XL and PZ conducted the bioinformatics analysis. XJL and XL provided useful comments and suggestions. LD and QX analyzed the data and wrote the paper.

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Correspondence to Lei Dong.

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Human tumor samples used in this paper were collected under informed consent as per approved Human Medical Ethics Review protocols at Xiangya Hospital and Beijing Institute of Technology.

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Xia, Q., Zhang, H., Zhang, P. et al. Oncogenic Smurf1 promotes PTEN wild-type glioblastoma growth by mediating PTEN ubiquitylation. Oncogene (2020). https://doi.org/10.1038/s41388-020-01400-1

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