Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

NSD2 promotes tumor angiogenesis through methylating and activating STAT3 protein

Oncogene volume 40, pages 2952–2967 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Data availability

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

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

    Da Song, Jingqin Lan, Yaqi Chen, Anyi Liu, Qi Wu, Yongdong Feng, Xuelai Luo, Zhixin Cao, Xiaonian Cao, Junbo Hu & Guihua Wang

  2. Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jingqin Lan

  3. Proteinomics Facility at Technology Center for Protein Sciences, Tsinghua University, Beijing, China

    Chongchong Zhao

  4. Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jing Wang

  5. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiaonian Cao

Authors
  1. Da Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingqin Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaqi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anyi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chongchong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongdong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuelai Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhixin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaonian Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Junbo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Guihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01747-z

This article is cited by

Search

Advanced search

Quick links