BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma.
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Authors
Lazarus, Kyren A
Zambon, Elisabetta
Watson, Julie
Correia, Lucia L
Das, Madhumita
Ugur, Rosemary
Pensa, Sara
Becker, Lukas
Campos, Lia S
Le Quesne, John
Calado, Dinis
Publication Date
2018-08-20Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
9
Issue
1
Pages
3327
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Lazarus, K. A., Hadi, F., Zambon, E., Bach, K., Santolla, M., Watson, J., Correia, L. L., et al. (2018). BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma.. Nat Commun, 9 (1), 3327. https://doi.org/10.1038/s41467-018-05790-5
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.
Keywords
Lung, Organoids, Cell Line, Tumor, Animals, Humans, Mice, Carcinoma, Squamous Cell, Lung Neoplasms, Histone-Lysine N-Methyltransferase, Carrier Proteins, Nuclear Proteins, Repressor Proteins, Cell Proliferation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Protein Binding, Oncogenes, SOXB1 Transcription Factors, Gene Knockdown Techniques, Genetic Loci
Sponsorship
Cancer Research UK (CRUK) - C47525/A17348
Funder references
Cancer Research UK (17348)
Cancer Research UK (25850)
Isaac Newton Trust (16.38(c))
National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/N002369/1)
Cancer Research UK (19013)
European Research Council (679411)
Biotechnology and Biological Sciences Research Council (BB/M00015X/2)
Medical Research Council (MC_PC_12009)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-05790-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280493
Rights
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