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Transcriptional control and signal transduction, cell cycle

RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

Leukemia volume 31, pages 2219–2227 (2017)Cite this article

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Abstract

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

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Acknowledgements

S-BN was supported by the Singapore Ministry of Health’s National Medical Research Council Transition Award (NMRC/TA/0020/2013). This work is supported in part by Singapore Ministry of Education Academic Research Fund Tier 1 (WBS No: R-179-000-046-112). W-JC was supported by the Singapore Ministry of Health’s National Medical Research Council Clinician Scientist Investigator Award. Ethics approval was obtained from IRB, National University of Singapore, ID: 10‐107.

Author contributions

W-JC conceived and designed study, and analyzed the data; S-BN conceived and designed the study, analyzed the data and wrote the paper. VS performed experiments and wrote the paper; GSSN, MO, JY, DC-CV and YI provided vital reagents and interpreted findings; T-HC performed bioinformatics analysis; MFH, MS-T, S-NC and SF constructed TMA, performed IHC and DIF; NS maintained and contributed cell lines.

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Author notes

  1. W-J Chng and S-B Ng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    V Selvarajan, S-N Choo, S Fan & S-B Ng

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    M Osato, G S S Nah, J Yan, T-H Chung, Y Ito, M Salto-Tellez, W-J Chng & S-B Ng

  3. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    M Osato

  4. Institute for Frontier Science Initiative, Kanazawa University, Japan

    D C-C Voon

  5. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    D C-C Voon

  6. Department of Anatomical Pathology, Faculty of Medicine, University of Indonesia, West Java, Indonesia

    M F Ham

  7. School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK

    M Salto-Tellez

  8. Department of Virology, Tokyo Medical and Dental University, Tokyo, Japan

    N Shimizu

  9. Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore

    W-J Chng

  10. Department of Pathology, National University Hospital, National University Health System, Singapore

    S-B Ng

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  1. V Selvarajan
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Correspondence to W-J Chng or S-B Ng.

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Selvarajan, V., Osato, M., Nah, G. et al. RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC. Leukemia 31, 2219–2227 (2017). https://doi.org/10.1038/leu.2017.40

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