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

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. Campos, Graham Ladds, Pentao Liu, Gerard I. Evan, Frank M. McCaughan, John Quesne, Joo-Hyeon Lee, Dinis Calado and Walid T. Khaled ()
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Kyren A. Lazarus: University of Cambridge
Fazal Hadi: University of Cambridge
Elisabetta Zambon: University of Cambridge
Karsten Bach: University of Cambridge
Maria-Francesca Santolla: University of Cambridge
Julie K. Watson: University of Cambridge
Lucia L. Correia: University of Cambridge
Madhumita Das: Lancaster Road
Rosemary Ugur: University of Cambridge
Sara Pensa: University of Cambridge
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
Joo-Hyeon Lee: University of Cambridge
Dinis Calado: The Francis Crick Institute
Walid T. Khaled: University of Cambridge

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05790-5

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