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:

WSTF acetylation by MOF promotes WSTF activities and oncogenic functions

Oncogene volume 39, pages 5056–5067 (2020)Cite this article

Subjects

Abstract

Williams syndrome transcription factor (WSTF) is a transcription factor and tyrosine kinase. WSTF overexpression promotes migration and proliferation of various cancers, and Ser158 (WSTFS158) phosphorylation plays an important role in this process. However, the role of the other posttranslational modifications of WSTF is unknown. Here, we report that lysine (K) 426 on WSTF is acetylated by MOF and deacetylated by SIRT1. Mechanistically, male-specific lethal (MSL) 1v1 interaction with WSTF facilitates its interaction with MOF for WSTF acetylation, which in turn promotes WSTFS158 phosphorylation. The kinase and transcriptional regulatory activity of WSTF were enhanced by acetylation. WSTFK426ac levels positively and significantly correlated with tumor size, histological grade, and age. Moreover, we demonstrated that acetylated WSTF promotes cancer cell proliferation, migration, invasion, and tumor formation. In conclusion, we identified the enzymes regulating WSTF K426 acetylation, and demonstrated an acetylation-dependent mechanism that modulates the activities of WSTF and contributes to tumorigenesis. Our findings provide new clues to study WSTF-mediated normal development and disease.

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: WSTF is acetylated by MOF in breast cancer cells.
Fig. 2: WSTF K426 is acetylated by MOF and this effect is enhanced by MSL1v1.
Fig. 3: WSTF K426 is deacetylated by SIRT1.
Fig. 4: Acetylation enhances WSTF kinase activity.
Fig. 5: Acetylation enhances WSTF transcriptional regulatory activity.
Fig. 6: Acetylation of WSTF promotes tumorigenesis.

Similar content being viewed by others

References

  1. Barnett C, Krebs JE. WSTF does it all: a multifunctional protein in transcription, repair, and replication. Biochem Cell Biol. 2011;89:12–23.

    Article  CAS  Google Scholar 

  2. Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature. 2009;457:57–62.

    Article  CAS  Google Scholar 

  3. Liu Y, Wang SQ, Long YH, Chen S, Li YF, Zhang JH. KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway. Oncotarget. 2016;7:53153–64.

    Article  Google Scholar 

  4. Lundqvist J, Kirkegaard T, Laenkholm AV, Duun-Henriksen AK, Bak M, Feldman D, et al. Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1alpha,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 2018;177:171–8.

    Article  CAS  Google Scholar 

  5. Meng J, Zhang XT, Liu XL, Fan L, Li C, Sun Y, et al. WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways. Cell Signal. 2016;28:1673–82.

    Article  CAS  Google Scholar 

  6. Wang YQ, Liu Y, Li YF, Zhang JH, Liu YK, Li YH, et al. Williams syndrome transcription factor is a target of pro-oncogenic Ser158 phosphorylation mediated by Ras-MAPK pathway in human breast cancer. Int J Clin Exp Pathol. 2016;9:1668–75.

    CAS  Google Scholar 

  7. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834–40.

    Article  CAS  Google Scholar 

  8. Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 2000;19:1176–9.

    Article  CAS  Google Scholar 

  9. Kahali B, Gramling SJ, Marquez SB, Thompson K, Lu L, Reisman D. Identifying targets for the restoration and reactivation of BRM. Oncogene. 2014;33:653–64.

    Article  CAS  Google Scholar 

  10. Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 2004;32:959–76.

    Article  CAS  Google Scholar 

  11. Li X, Wu L, Corsa CA, Kunkel S, Dou Y. Two mammalian MOF complexes regulate transcription activation by distinct mechanisms. Mol Cell. 2009;36:290–301.

    Article  CAS  Google Scholar 

  12. Su J, Wang F, Cai Y, Jin J The Functional Analysis of Histone Acetyltransferase MOF in Tumorigenesis. Int J Mol Sci. 2016;17:99. https://doi.org/10.3390/ijms17010099.

  13. Pfister S, Rea S, Taipale M, Mendrzyk F, Straub B, Ittrich C, et al. The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int J Cancer. 2008;122:1207–13.

    Article  CAS  Google Scholar 

  14. Liu Y, Wang DL, Chen S, Zhao L, Sun FL. Oncogene Ras/phosphatidylinositol 3-kinase signaling targets histone H3 acetylation at lysine 56. J Biol Chem. 2012;287:41469–80.

    Article  CAS  Google Scholar 

  15. Wan J, Xu W, Zhan J, Ma J, Li X, Xie Y, et al. PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6. Nucleic Acids Res. 2016;44:10662–75.

    Article  CAS  Google Scholar 

  16. Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009;458:591–6.

    Article  CAS  Google Scholar 

  17. Liu Y, Long YH, Wang SQ, Zhang YY, Li YF, Mi JS, et al. JMJD6 regulates histone H2A.X phosphorylation and promotes autophagy in triple-negative breast cancer cells via a novel tyrosine kinase activity. Oncogene. 2019;38:980–97.

    Article  CAS  Google Scholar 

  18. Das C, Lucia MS, Hansen KC, Tyler JK. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature. 2009;459:113–7.

    Article  CAS  Google Scholar 

  19. Liu Y, Xing ZB, Wang SQ, Chen S, Liu YK, Li YH, et al. MDM2-MOF-H4K16ac axis contributes to tumorigenesis induced by Notch. FEBS J. 2014;281:3315–24.

    Article  CAS  Google Scholar 

  20. Liu Y, Xing ZB, Zhang JH, Fang Y. Akt kinase targets the association of CBP with histone H3 to regulate the acetylation of lysine K18. FEBS Lett. 2013;587:847–53.

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number 81772834); Natural Science Foundation of Hebei Province (grant number H2019105034); Science Fund for Distinguished Young Scholars of North China University of Science and Technology (JQ201704); Doctoral Research Project of North China University of Science and Technology; the Program for Innovation Research Team (in Science and Technology) of Tangshan (17130205D).

Author information

Author notes

  1. These authors contributed equally: Yan Liu, Yuan-Yue Zhang, Shu-Qing Wang, Yue-Hong Long

Authors and Affiliations

  1. College of Life Science, North China University of Science and Technology, Tangshan, China

    Yan Liu, Yuan-Yue Zhang & Yue-Hong Long

  2. Cancer Institute, Affiliated Tangshan People’s Hospital of North China University of Science and Technology, Tangshan, China

    Yan Liu, Yuan-Yue Zhang, Yu-Feng Li, Yan-Kun Liu, Ya-Qi Wang & Jing-Hua Zhang

  3. Graduate School of North China University of Science and Technology, Tangshan, China

    Yuan-Yue Zhang

  4. Hospital of North China University of Science and Technology, Tangshan, China

    Shu-Qing Wang

  5. Orthopaedic Surgery, North China University of Science and Technology Affiliated Hospital, Tangshan, China

    Min Li

  6. Neurosurgery, Affiliated Tangshan People’s Hospital of North China University of Science and Technology, Tangshan, China

    Yu-Hui Li

  7. Zunhua People’s Hospital, Zunhua, China

    Jiang-Sheng Mi, Cheng-Hua Yu, De-Yan Li & Xiao-Jun Zhang

Authors
  1. Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan-Yue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu-Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yue-Hong Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan-Kun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Hui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ya-Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiang-Sheng Mi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cheng-Hua Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. De-Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jing-Hua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiao-Jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XJZ and JHZ had the idea for the experiment and supervised the project. YL, YYZ, YHL, SQW, ML, YQW and YFL, YKL, YHL, JSM, CHY, and DYL carried out the experiment. YL, SQW, and YHL wrote the manuscript.

Corresponding authors

Correspondence to Yu-Feng Li, Jing-Hua Zhang or Xiao-Jun Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Liu, Y., Zhang, YY., Wang, SQ. et al. WSTF acetylation by MOF promotes WSTF activities and oncogenic functions. Oncogene 39, 5056–5067 (2020). https://doi.org/10.1038/s41388-020-1350-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-1350-0

This article is cited by

Search

Advanced search

Quick links