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EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms

Oncogene volume 37, pages 461–477 (2018)Cite this article

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Abstract

Recently, we reported that the histone methyltransferase, EZH2, controls leukocyte migration through interaction with the cytoskeleton remodeling effector, VAV, and direct methylation of the cytoskeletal regulatory protein, Talin. However, it is unclear whether this extranuclear, epigenetic-independent function of EZH2 has a profound impact on the initiation of cellular transformation and metastasis. Here, we show that EZH2 increases Talin1 methylation and cleavage, thereby enhancing adhesion turnover and promoting accelerated tumorigenesis. This transforming capacity is abolished by targeted disruption of EZH2 interaction with VAV. Furthermore, our studies demonstrate that EZH2 in the cytoplasm is closely associated with cancer stem cell properties, and that overexpression of EZH2, a mutant EZH2 lacking its nuclear localization signal (EZH2ΔNLS), or a methyl-mimicking Talin1 mutant substantially promotes JAK2-dependent STAT3 activation and cellular transformation. Taken together, our results suggest a critical role for the VAV interaction-dependent, extranuclear action of EZH2 in neoplastic transformation.

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Acknowledgements

We thank S Strömblad for critical reading, discussions and comments on the manuscript; Y Zhang (Harvard University) for the EZH2, SUZ12 and EED baculovirus expression vectors; we thank Y Or for providing BALB/c mice and technical support, LY Lu for advice on statistical analysis and A Sullivan from Obrizus Communications for editing the manuscript. This work was supported by the Singapore Agency for Science Technology and Research (A*STAR) through a Biomedical Research Council (BMRC) grant (10/1/22/19/666) to LN, Singapore Ministry of Education (MOE2009-T2-1-034 and MOE2013-T2-2-038) and Ministry of Health, National Medical Research Council (NMRC-CBRG/0057/201) to I-hS.

Author contributions

NV identified EZH2-mediated Talin methylation sites, initiated the project and established essential collaborations; NV and JFW designed and conducted most of the experiments, including the in vitro methyltransferase assays, identification of the EZH2–VAV interaction mutant and performed experiments in mammary epithelial cells, breast cancer animal models and were also involved in the data interpretation and manuscript preparation; KPT and MSM did computational modeling and predicted residues critical for EZH2–VAV interaction; HHC and VCLL were involved in experiments using breast cancer animal models; EC and JG performed differential expression analysis of RNA-seq data; YHY and SGS performed the SPR analysis; AA and LN produced recombinant octamers and I-hS designed and interpreted the experiments and wrote the manuscript.

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  1. N Venkatesan and J F Wong: These two authors contributed equally to this work.

Authors and Affiliations

  1. School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore

    N Venkatesan, J F Wong, H H Chung, Y H Yau, A Allahverdi, L Nordenskiöld, S Geifman-Shochat, V C L Lin & I-h Su

  2. Bioinformatics Institute, Agency for Science, Technology and Research, Biopolis, Republic of Singapore

    K P Tan & M S Madhusudhan

  3. School of Computer Engineering, Nanyang Technological University, Republic of Singapore

    K P Tan

  4. Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Republic of Singapore

    E Cukuroglu & J Göke

  5. National Cancer Centre Singapore, Republic of Singapore

    J Göke

  6. Indian Institute of Science Education and Research, Pune, India

    M S Madhusudhan

  7. Department of Biological Sciences, National University of Singapore, Republic of Singapore

    M S Madhusudhan

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  1. N Venkatesan
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Venkatesan, N., Wong, J., Tan, K. et al. EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms. Oncogene 37, 461–477 (2018). https://doi.org/10.1038/onc.2017.309

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