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NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein

Abstract

Tumor angiogenesis plays vital roles in tumorigenesis and development; regulatory mechanism of angiogenesis is still not been fully elucidated. NSD2, a histone methyltransferase catalyzing di-methylation of histone H3 at lysine 36, has been proved a critical molecule in proliferation, metastasis, and tumorigenesis. But its role in tumor angiogenesis remains unknown. Here we demonstrated that NSD2 promoted tumor angiogenesis in vitro and in vivo. Furthermore, we confirmed that the angiogenic function of NSD2 was mediated by STAT3. Momentously, we found that NSD2 promoted the methylation and activation of STAT3. In addition, mass spectrometry and site-directed mutagenesis assays revealed that NSD2 methylated STAT3 at lysine 163 (K163). Meanwhile, K to R mutant at K163 of STAT3 attenuated the activation and angiogenic function of STAT3. Taken together, we conclude that methylation of STAT3 catalyzed by NSD2 promotes the activation of STAT3 pathway and enhances the ability of tumor angiogenesis. Our findings investigate a NSD2-dependent methylation–phosphorylation regulation pattern of STAT3 and reveal that NSD2/STAT3/VEGFA axis might be a potential target for tumor therapy.

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Fig. 1: NSD2 is overexpressed in altered carcinomas.
Fig. 2: Inhibition of NSD2 moderates tumor-induced angiogenesis in vivo and in vitro.
Fig. 3: NSD2 influences the activation of the STAT3 signaling pathway.
Fig. 4: The angiogenic function of NSD2 is mediated by STAT3.
Fig. 5: STAT3 inhibitor STATTIC abolishes angiogenic function of NSD2 in vivo.
Fig. 6: NSD2 directly interacts with and methylates STAT3 to activate the STAT3 signaling pathway.
Fig. 7: NSD2 methylates STAT3 at K163.
Fig. 8: Inhibition of methylation at K163 of STAT3 partially abolishes the angiogenic function of STAT3 in vitro and in vivo.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) with the dataset identifier PXD021336.

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Acknowledgements

We are grateful to the members in Guihua Wang’s lab and Junbo Hu’s lab for the critical inputs and suggestions. This work is supported by NSFC (No. 81773113 GW, No. 81922053 GW, No.81702264 XC, No. 81974432 GW, and No. 81874186 JH).

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GW conceived the project. GW and JH acquired funding and designed the majority of experiments. ZC and XL supervised the project and gave some advice. DS wrote the manuscript and performed most of the molecular biological experiments. JL analyzed the results. YC, AL, and QW performed most of the phenotype experiments. CZ did the mass spectrometry detection and analysis. YF and JW made their efforts in the bioinformatics analysis. XC made contributions and provided support in the process of revision.

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Correspondence to Junbo Hu or Guihua Wang.

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All patient specimens mentioned in this study were approved by the Ethics Committee of Tongji Hospital following the Declaration of Helsinki and informed consents were signed before the operation. Animal experiments were performed strictly following the Animal Study Guideline of Huazhong University of Science and Technology.

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Song, D., Lan, J., Chen, Y. et al. NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein. Oncogene 40, 2952–2967 (2021). https://doi.org/10.1038/s41388-021-01747-z

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