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BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma

Author

Listed:
  • Kyren A. Lazarus

    (University of Cambridge
    Cambridge Cancer Centre)

  • Fazal Hadi

    (University of Cambridge
    Cambridge Cancer Centre)

  • Elisabetta Zambon

    (University of Cambridge
    Cambridge Cancer Centre)

  • Karsten Bach

    (University of Cambridge
    Cambridge Cancer Centre)

  • Maria-Francesca Santolla

    (University of Cambridge
    University of Calabria)

  • Julie K. Watson

    (University of Cambridge)

  • Lucia L. Correia

    (University of Cambridge)

  • Madhumita Das

    (Lancaster Road)

  • Rosemary Ugur

    (University of Cambridge
    Cambridge Cancer Centre)

  • Sara Pensa

    (University of Cambridge
    Cambridge Cancer Centre)

  • Lukas Becker

    (University of Cambridge)

  • Lia S. Campos

    (Wellcome Trust Sanger Institute)

  • Graham Ladds

    (University of Cambridge)

  • Pentao Liu

    (Wellcome Trust Sanger Institute)

  • Gerard I. Evan

    (University of Cambridge)

  • Frank M. McCaughan

    (University of Cambridge)

  • John Quesne

    (Lancaster Road
    University of Leicester
    University Hospitals Leicester NHS trust)

  • Joo-Hyeon Lee

    (University of Cambridge)

  • Dinis Calado

    (The Francis Crick Institute)

  • Walid T. Khaled

    (University of Cambridge
    Cambridge Cancer Centre
    University of Cambridge)

Abstract

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8. We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A–SOX2 transcriptional programme as a novel candidate for drug development.

Suggested Citation

  • Kyren A. Lazarus & Fazal Hadi & Elisabetta Zambon & Karsten Bach & Maria-Francesca Santolla & Julie K. Watson & Lucia L. Correia & Madhumita Das & Rosemary Ugur & Sara Pensa & Lukas Becker & Lia S. Ca, 2018. "BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05790-5
    DOI: 10.1038/s41467-018-05790-5
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