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NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein


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 ( with the dataset identifier PXD021336.


  1. 1.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  Google Scholar 

  2. 2.

    Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol cell Biol. 2007;8:464–78.

    CAS  PubMed  Google Scholar 

  3. 3.

    De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457–74.

    PubMed  Google Scholar 

  4. 4.

    Canavese M, Ngo DT, Maddern GJ, Hardingham JE, Price TJ, Hauben E. Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer. Int J Cancer. 2017;140:2183–91.

    CAS  PubMed  Google Scholar 

  5. 5.

    Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010;116:4720–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Stratman AN, Davis MJ, Davis GE. VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines. Blood. 2011;117:3709–19.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Saltz LB. Bevacizumab in colorectal cancer: it should have worked. Lancet Oncol. 2016;17:1469–70.

    PubMed  Google Scholar 

  8. 8.

    Smeets D, Miller IS, O’Connor DP, Das S, Moran B, Boeckx B, et al. Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy. Nat Commun. 2018;9:4112.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, et al. Resistance mechanisms to anti-angiogenic therapies in cancer. Front Oncol. 2020;10:221.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–21.

    CAS  PubMed  Google Scholar 

  11. 11.

    Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, et al. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci USA. 1996;93:3963–6.

    CAS  PubMed  Google Scholar 

  12. 12.

    Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yu H, Jove R. The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ. Targeting Janus kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and cancer: rationale, progress, and caution. Pharmacol Rev. 2020;72:486–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci USA. 2010;107:21499–504.

    CAS  PubMed  Google Scholar 

  16. 16.

    Dasgupta M, Dermawan JK, Willard B, Stark GR. STAT3-driven transcription depends upon the dimethylation of K49 by EZH2. Proc Natl Acad Sci USA. 2015;112:3985–90.

    CAS  PubMed  Google Scholar 

  17. 17.

    Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013;23:839–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Luo J, Wang K, Yeh S, Sun Y, Liang L, Xiao Y, et al. LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling. Nat Commun. 2019;10:2571.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307:269–73.

    CAS  PubMed  Google Scholar 

  20. 20.

    Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell. 2011;44:609–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, et al. WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum Mol Genet. 1998;7:1071–82.

    CAS  PubMed  Google Scholar 

  22. 22.

    Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009;460:287–91.

    CAS  PubMed  Google Scholar 

  23. 23.

    Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–98.

    CAS  PubMed  Google Scholar 

  24. 24.

    Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998;92:3025–34.

    CAS  PubMed  Google Scholar 

  25. 25.

    Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood. 2005;105:4060–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Foltz SM, Gao Q, Yoon CJ, Sun H, Yao L, Li Y, et al. Evolution and structure of clinically relevant gene fusions in multiple myeloma. Nat Commun. 2020;11:2666.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zhang J, Lee YR, Dang F, Gan W, Menon AV, Katon JM, et al. PTEN methylation by NSD2 controls cellular sensitivity to DNA damage. Cancer Discov. 2019;9:1306–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiær E, Rossing HH, Johansen JV, et al. The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res. 2011;17:2919–33.

    CAS  PubMed  Google Scholar 

  29. 29.

    Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Stubbs M, Burn T, Sparks R, Maduskuie T, Diamond S, Rupar M. et al. The novel bromodomain and extraterminal domain inhibitor INCB054329 induces vulnerabilities in myeloma cells that inform rational combination strategies. Clin Cancer Res. 2019;25:300–11.

    CAS  PubMed  Google Scholar 

  31. 31.

    Biggar KK, Li SS. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol. 2015;16:5–17.

    CAS  PubMed  Google Scholar 

  32. 32.

    Zhang X, Huang Y, Shi X. Emerging roles of lysine methylation on non-histone proteins. Cell Mol Life Sci. 2015;72:4257–72.

    CAS  PubMed  Google Scholar 

  33. 33.

    Hamamoto R, Saloura V, Nakamura Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat Rev Cancer. 2015;15:110–24.

    CAS  PubMed  Google Scholar 

  34. 34.

    Wang G, Long J, Gao Y, Zhang W, Han F, Xu C, et al. SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. Nat Cell Biol. 2019;21:214–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Guo J, Dai X, Laurent B, Zheng N, Gan W, Zhang J, et al. AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions. Nat cell Biol. 2019;21:226–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hou Z, Sun L, Xu F, Hu F, Lan J, Song D, et al. Blocking histone methyltransferase SETDB1 inhibits tumorigenesis and enhances cetuximab sensitivity in colorectal cancer. Cancer Lett. 2020;487:63–73.

    CAS  PubMed  Google Scholar 

  37. 37.

    Park JW, Chae YC, Kim JY, Oh H, Seo SB. Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. Oncogene. 2018;37:6212–24.

    CAS  PubMed  Google Scholar 

  38. 38.

    Lhoumaud P, Badri S, Rodriguez-Hernaez J, Sakellaropoulos T, Sethia G, Kloetgen A, et al. NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nat Commun. 2019;10:4843.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Cheong CM, Mrozik KM, Hewett DR, Bell E, Panagopoulos V, Noll JE, et al. Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma. Cancer Lett. 2020;475:99–108.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    He C, Liu C, Wang L, Sun Y, Jiang Y, Hao Y. Histone methyltransferase NSD2 regulates apoptosis and chemosensitivity in osteosarcoma. Cell Death Dis. 2019;10:65.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wang JJ, Zou JX, Wang H, Duan ZJ, Wang HB, Chen P, et al. Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling. Acta Pharmacologica Sin. 2019;40:1067–75.

    CAS  Google Scholar 

  42. 42.

    Aytes A, Giacobbe A, Mitrofanova A, Ruggero K, Cyrta J, Arriaga J, et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat Commun. 2018;9:5201.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Xie Z, Chooi JY, Toh SHM, Yang D, Basri NB, Ho YS, et al. MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. Leukemia. 2019;33:739–48.

    CAS  PubMed  Google Scholar 

  44. 44.

    Swaroop A, Oyer JA, Will CM, Huang X, Yu W, Troche C, et al. An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene. 2019;38:671–86.

    CAS  PubMed  Google Scholar 

  45. 45.

    Wang X, Spandidos A, Wang H, Seed B. PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update. Nucleic Acids Res. 2012;40:D1144–9. Database issue.

    CAS  PubMed  Google Scholar 

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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).

Author information




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.

Corresponding authors

Correspondence to Junbo Hu or Guihua Wang.

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The authors declare no competing interests.

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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).

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